Animal Models of Neurodegenerative Diseases

Handbook of Neurochemistry and Molecular Neurobiology 3rd Edition Vol. 26 Neurochemical Mechanisms in Disease

Animal Models of Neurodegenerative Diseases Imad GHORAYEB1, Guylène PAGE2, Afsaneh GAILLARD3, Mohamed JABER3*

1

Université de Bordeaux II, CNRS 5227, 146 rue Léo Saignat, 330776 Bordeaux Cedex-

FRANCE. 2Groupe de Recherche sur le Vieillissement Cerebral (GReViC), EA 3808, Université de Poitiers, 40 av. du recteur Pineau, 86022 Poitiers Cedex-FRANCE. 3Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS 6187, 40 av. Du recteur Pineau, 86022 Poitiers Cedex-FRANCE. *

To whom all correspondence should be addressed. Tel: 33-549-453-985. Fax: 3-549-454-

014. Email: [email protected]

Acknowledgements: GP wishes to thank AIRMA (Association Internationale pour la Recherche sur la Maladie d’Alzheimer), the LECMA (Ligue Européenne Contre la Maladie d’Alzheimer) and The Poitiers University Hospital. Work on animal models of neurodegenerative disorders in the group of MJ and AG is financed by the Fondation de France, Institut pour la Recherche sur la Moelle Epinière and the CNRS interdisciplinary program “Aging”. Key words : Parkinson’s disease, Huntington disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Multiple system atrophy, Tauopathies, nucleotide repeats.

CHAPTER INDEX INTRODUCTION 1. ALZHEIMER’S DISEASE 1.1. The human disease 1.2. Rodent models 1.2.1 Pharmacological models of Alzheimer’s disease 1.2.2. Trangenic mouse models of Alzheimer’s disease 1.2.2.1. APP mice 1.2.2.2. APP/PS-1 mice 1.2.2.3. APP/BACE mice 1.2.2.4. APP/ApoE mice 1.2.2.5. APP/ADAM mice 1.2.2.6. Tau and Tau/APP mice 1.2.3. Trangenic rat models of Alzheimer’s disease 1.3. Invertebrate models 1.4. Primate models 1.4.1. Spontaneous approaches 1.4.2. Lesioning approaches 1.4.3. Pharmacological approaches 1.5. Perspectives 2. PARKINSON’S DISEASE 2.1. The human disease 2.2. Rodent animal models 2.2.1. The 6-OHDA model 2.2.1.1. Striatal injection 2.2.1.2. Medial forebrain bundle injection 2.2.1.3. Substantia nigra injection 2.2.1.4. Behavioural impairment following 6-OHDA lesions 2.2.2. The MPTP model 2.2.3. Genetic rodent models of PD 2.2.3.1. PD caused by mutations in the
-synuclein gene (PARK1) 2.2.3.2. PD caused by mutations in the parkin gene (PARK2) 2.2.3.3. PTEN-induced kinase-1 (PINK1) mutations 2.2.2.4. DJ-1 (PARK7) mutations 2.2.2.5. LRRK2/dardarin mutations 2.3. Non-human primate models 3. MULTIPLE SYSTEM ATROPHY 3.1. The human disease 3.2. Rodent animal models 3.3. Primate animal models

4. AMYOTROPHIC LATERAL SCLEROSIS 4.1. The human disease 4.2. Animal models

5. HUNTINGTON DISEASE

5.1 The human disease 5.2. Rodent Animal models 5.3. Invertebrate animal models 5.4. Primate animal models 5.4.1. Lesioning approaches 5.4.2 Genetic approaches

CONCLUSION BIBLIOGRAPHIE

INTRODUCTION Given the inherent complexity of neuronal systems and of disease process, animal models have become mandatory to Neuroscience research in general and to understand the pathogenesis of neurodegenerative diseases in particular. Indeed, investigation of human pathologies relies mostly on postmortem human brains and on clinical criteria that do not allow the identification of the causal chains that have lead to a disease nor the biological basis of a given pathology. Thus, animal models of neurodegenerative disorders have become a widespread laboratory “tool”. Use and housing of these models require animal facilities dedicated for research purposes and that are controlled by specific policies, guidelines and procedures at local, national, and international levels. Whatever the country and the regulations, the accreditation process is long and difficult to obtain and projects involving animal models are reviewed on regular basis to ensure of the animal welfare, the appropriateness of the species used for a given investigation, the adequacy of the experimental procedures with the postulated hypothesis and that a minimal number of animals is used for a given study. The use of primates is often dependant on the solidity of previous research performed in lower species such as rodents (mice and rats for the most) but also worms (Caenorhabditis elegans), flies (drosophila melanogaster) and zebrafish. Primate animal models are still an essential step before reaching human clinical research for obvious and frequently confirmed similarities between the two species be it behavioural (large clinical repertoire), anatomical, physiological or genetic. Major constraints of ethical, practical and cost nature have limited the use of primates to few specialized centers. Thus, the mainstream research in neurodegenerative disease has focused on rodents animal models that were used to better understand the pathology and the underlying biological mechanisms, develop standardized diagnosis (biological tests, identification of biomarkers…) and search for potential new treatments for these diseases. The use of rodent models was strengthened also given the possibility of performing genetic manipulations to mimic some of the genetic features of the diseases. Here, we will detail several animal models of neurodegenerative disorders with a special focus on the two major ones in humans, namely Parkinson’s and Alzheimer’s diseases. As will be detailed in this book chapter, some animal models can present spontaneous syndromes, often due to analogous mutations with the human disease but are

more generally obtained following toxin injections, physical (mechanical lesions), or genetic manipulations. Some animal models can mimic the behavioural consequences of a given neurodegenerative disease with drawbacks related to specific animal behavior that is only remotely related to humans. Disease gene-based model (also referred to as an “etiologic model”) can indeed reproduce the etiology of a genetically-determined form of a given disease, although adaptations that can occur following a genetic manipulation throughout development can be quit different between the animal and the human. Since manipulation of the mouse genome has become standardized and available at relatively moderate costs, the use the genetically altered mice strains to model neurodegenerative disorders has become increasingly widespread. This use will tend to be generalized following the publication of the assembled mouse genome sequence (Botcherby 2002). Transgenic mice can be generated to overexpress a gene to reproduce a gain of function mutation, to knock-out a gene for a non expression mutation and to mutate a gene to express an altered protein. Many other variances are available where a gene is silenced during development only or expressed/knocked-out in a specific brain area, for instance. These transgenic mice are used to map disease features, determine genetic and environmental factors that can precipitate disease progression, detail behavioural and cellular consequences of altering the expression of a disease related gene and test potential therapeutics. Meticulous gene manipulations have generated a wealth of information regarding the etiology of pathology, the identification of its biological basis and the behavioural consequences of such a manipulation. However, increasing concern is raised as to the adequacy of these animal models to human diseases. Indeed, it is safe to state early in this book chapter that animal models generated so far fail to reproduce faithfully the myriad of biochemical, cellular and behavioural changes reported in a given neurodegenerative disease in humans. The ideal animal model reproducing all hallmarks of a given neurodegenerative disorder is an unattainable aim, as it is expected to develop specific and reproducible behavioural symptoms and biological features related to the disease along with slow onset and selective cell loss. Instead, an animal model is considered acceptable when it demonstrates its usefulness in understanding the pathogenesis of a disease, it’s behavioural, cellular and molecular consequences and in exploring potential treatment avenues. This can sometimes be achieved even when animal models show striking differences with the human pathology. In this line, the general message that can be drawn throughout this review is that we have reached a point in research using animal models where it has become a pressing

necessity to standardize not only the experimental procedures used to obtain an animal model, but also the housing and breeding conditions, age and sex of the animals, qualitative and quantitative assessments of phenotypes investigated and, ultimately the interpretation of results obtained and their relevance to the pathology.

1. ALZHEIMER’S DISEASE 1.1. The human disease Late onset Alzheimer's disease (AD) is the most prevalent subtype of age-related dementia accounting for 60% of cases of dementia and with a mean prevalence estimate of 3·4% (Kalaria et al. 2008). If growth in the older population continues, it is projected that the prevalence of AD will nearly quadruple in the next 50 years, by which time approximately 1 in 45 individuals will be afflicted with the disease (Brookmeyer et al. 1998). In AD, neurodegeneration targets specific brain regions early in its course, especially cholinergic basal forebrain and medial temporal lobe structures. The sequential involvement of the posterior cingulated, temporal and parietal cortical regions completes the progression of the disease. The neuropathologic hallmarks of AD include massive neuronal cell and synapse loss at specific sites and the presence of senile plaques and neurofibrillary tangles (NFTs). The senile plaques are formed from deposits of amyloid-
peptide (A
) that is derived from the amyloid precursor protein (APP) whereas the NFTs contain hyperphosphorylated microtubule-associated protein (MAP) tau. Phosphorylation of both APP and tau represents a biochemical link between the two characteristic lesions of AD (Duyckaerts et al. 2008). Most AD cases occur sporadically (SAD), although inheritance of certain susceptibility genes enhances the risk. In early-onset familial AD (FAD), which accounts for less than 5% of the total number of AD cases, autosomal dominant mutations have been identified in three genes: APP, presenilin 1 (PS-1) and presenilin 2 (PS-2), each of which leads to an overabundance of A
(Gotz and Ittner 2008). The presenilins are components of the proteolytic -secretase complex that, together with
-secretase, generates A
fragments from the cleavage of APP. Most FAD cases are caused by mutations in PSEN1 and PSEN2, of which over 130 have been identified. In SAD, various susceptibility genes have been identified, including apolipoprotein E (ApoE). It is actually considered that the genetic risk factor that accounts for more cases of AD than any other is the ApoE4 allele located on chromosome 19 (Bertram and Tanzi 2008). Since neuropathologic confirmation is required for the diagnosis of definite AD, only diagnosis of probable and possible AD can be made in living patients according to the

commonly used criteria for the diagnosis of AD. These include progressive memory loss with cognitive deficits in at least two cognitive domains (McKhann et al. 1984). As the disease progresses, the characteristic clinical features of aphasia, apraxia and agnosia emerge along with consequent amnesia and personality changes. At present, there are no known curative or preventive measures for AD and current symptomatic treatments of AD are of limited benefit, as they are not directed at the underlying biological basis of the disease.

1.2. Rodent models The identification of the genetics defects and mutations that causes FAD, has led to the generation of transgenic rodent models of AD. Nowadays, mice are the most popular animal models for AD, although rat models are developed as well. Furthermore, invertebrate models of AD have been developed and will be presented at the end of this section. 1.2.1 Pharmacological models of Alzheimer’s disease A
neurotoxicity is studied in rodents (mouse and rat) after intracerebral injections of A
peptides (A
1-40/42, A
22/25-35) previously fibrillary aggregated by incubation at 37°C during 4 days minimum. Usually, rodents are intracerebroventriculary injected with a dose range between 3-9 nmol for a mouse and a dose of 15 nmol for a rat (Maurice et al. 1996); (Stepanichev et al. 2003). Some authors injected the aggregated A
peptide directly into hippocampus or into frontal and cingulated cortices uni- or bilaterally (Cetin and Dincer 2007; Gonzalo-Ruiz et al. 2006). Examination of Congo red-stained tissue sections demonstrated the presence of numerous amyloid deposits throughout the brain areas and a decrease in cresyl violet-stained cells indicating a significant cell loss. Furthermore, A
injected mice showed learning and memory deficits after one week post-injection (Fu et al. 2006; Gonzalo-Ruiz et al. 2006; Maurice et al. 1996; Stepanichev et al. 2003). While these A
-injected rodent models did not encompass all of the neuropathological effects observed in AD, they are useful to understand the toxicity of amyloid deposits, in particular in the cholinergic system, and to screen for neuroprotective molecules active on the amyloid process (Fu et al. 2006; Gonzalo-Ruiz et al. 2006). 1.2.2. Trangenic mouse models of Alzheimer’s disease 1.2.2.1. APP mice After the first discovery of the mutation in the APP gene by Hardy et al. (Hardy and Allsop 1991), authors described the first NSEAPP mouse model of AD (Quon et al. 1991).

Then, other human APP transgenics have been developed: PDAPP, Tg2576, APP23, TgCRND8 and J20. The APP transgene carried one or two mutations at the
-secretase site (Swedish mutation) or/and at the -secretase site (London mutation) and was driven by various mouse promoters for genes coding for neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), the prion protein (Prp) or thymus antigen (Thy-1.2). For Thy-1.2, the thymus-specific intronic regulatory element has been removed to target expression specifically to the mouse brain (Andra et al. 1996). Most app transgenes utilize a cDNA encoding the APP695 isoform, which is the predominant species expressed in brain, or the longer APP751 species. Excepted for NSEAPP mice that show diffuse (preamyloid) plaques, all others displayed amyloid plaques which resembled the mature (neuritic) plaques characteristic of AD with positive thioflavin-S staining. These amyloid deposits were observed at 6-12 months according to the model from the hippocampus to cortical and limbic areas in a progressive manner showing regional specificity like that seen in AD pathology. In TgCRND8 mice expressing both the Swedish and London mutations under the Prp promoter, thioflavine-S-positive amyloid deposits became evident by 3 months of age (Chishti et al. 2001). The amyloid plaques were associated with dystrophic neurites, gliosis and synaptic loss only in PDAPP mice. Despite the extent of amyloid burden, clear neurodegeneration has not been demonstrated except in the hippocampal CA1 region (14% of neuronal loss) of 1418-month-old APP23 mice with an apparent correlation with senile plaques load (Calhoun et al. 1999). While a positive immunoreactivity of phosphorylated tau protein was detected, no paired-helicoidal filament (PHFs) was noted in these transgenic APP mice. To date, it seems that the APP23 mice are the only strain to show a cerebral amyloid angiopathy (CAA). Clinically, the A
form of CAA is a significant contributor to haemorrhagic stroke, and up to 90% of AD patients may develop CAA over the disease course. Modest cholinergic deficits have also been reported in aged APP23 mice (Boncristiano et al. 2002). Behavioural studies described age-dependent cognitive deficits assessed by using a Morris water maze. This behavioural test measures spatial reference memory. In these transgenic APP mice, both their acquisition of hidden platform locations and their retention of spatial reference information are affected (Table 1). 1.2.2.2. APP/PS-1 mice Most FAD cases are caused by the mutations in PS-1 and PS-2. Presenilins are polytopic transmembrane proteins which are, in combination with three or other proteins (aph-1, pen-2 and nicastrin), required for an efficient - secretase complex and activity to generate amyloid

peptides (Edbauer et al. 2003). Although pathogenic mutations in APP and presenilins do not co-exist in human AD, it was tempting to cross APP and PS-1 mutant mice and to assess whether mutant PS-1 would cause elevated A
levels. Overexpression alone of PS-1 M146L, M146V FAD-associated mutations induced a selective increase of A
42 production. Crossing APP transgenic mice with PS-1 mutant mice causes an elevation of A
42/A
40 levels and an acceleration of amyloid deposits by 4 months of age in APPSWE/PS-1dE9 mice (Garcia-Alloza et al. 2006) by 6 months of age in PSAPP (Tg2576 mouse x PS-1M146L mouse) compared to 9 months in Tg2576 mice and by 1 month of age in TgCRND8/PS-1 mice compared to 3 months TgCRND8 mice (Chishti et al. 2001; Holcomb et al. 1998). In various double APP/PS-1 transgenic mice, no clear evidence for neurodegeneration in either frontal cortex or CA1 hippocampus was evident except in the model APPSL/PS-1M146L mice developed by Blanchard et al. (Blanchard et al. 2003) where a loss (35%) of neurons in the pyramidal cell layer of the hippocampus was seen at 17 months of age (Schmitz et al. 2004). Recently, an intense subcortical monoaminergic neurodegeneration (50% neuronal loss) was observed in APPSWE/PS-1dE9 (Liu et al. 2008b). It is to be noted that none of these mouse models show any NFTs. However, many studies described behavioural phenotype in various APP/PS-1 transgenic mice (Higgins and Jacobsen 2003; Janus and Westaway 2001; Reiserer et al. 2007; Savonenko et al. 2005). In particular, the performance on the Y-maze, that measures spatial working memory, was impaired before amyloid deposits in PSAPP mice (Holcomb et al. 1999). Taken together, these findings show that it is difficult to obtain a mouse model reproducing perfectly AD, especially with both the neuronal loss and NFTs. However, Casas et al. (Casas et al. 2004) produced a new model with many features of AD, the APPSL/PS-1 knock-in mice. These transgenic mice have two mutations in human APP gene at K670N/M671L and V717I sites corresponding to
- and -secretase sites, respectively. In addition, their endogenous ps-1 gene carries the M233T and L235P mutations known to be linked to very early onset FAD at 29 and 35 years of age, respectively. These mice displayed a massive neuronal loss (49% in the 10-month-old APPSL/PS-1 KI mice) in the CA1 region of the hippocampus with an intense neuronal apoptosis (Casas et al. 2004; Page et al. 2006). This neuronal loss distribution closely parallels the strong intraneuronal A
immunostaining and intracellular thioflavine-S-positive material but does not correlate with extracellular deposits (Christensen et al. 2008b). Furthermore, the authors described also a loss of neurons (44%) in the dendate gyrus granule layer (Cotel et al. 2008). The APPSL/PS-1 KI mouse model exhibits early

robust brain and spinal cord axonal degeneration (Wirths et al. 2007; Wirths et al. 2006). At the same time-point, a dramatic age-dependent reduced ability to perform working memory and motor tasks is observed. These mice are smaller and show development of a thoracolumbar kyphosis, together with an incremental loss of body weight (Wirths et al. 2008b). Onset of the observed behavioural alterations correlates well with robust axonal degeneration in brain and spinal cord and with abundant hippocampal CA1 neuron loss (Bayer and Wirths 2008). While, our group detected hyperphosphorylated tau protein in cell bodies of neurons in 11-month-old APPSL/PS-1 KI mice (unpublished data obtained by G Page), NFTs were not reported yet. Contrary to studies showing a minor loss of cholinergic interneurones in the motor cortex of APPSWE/PS-1(deltaE9) mice (Perez et al. 2007), the APPSL/PS-1 KI mouse model shows a loss of choline acetyl transferase-positive neurons only in the motor nuclei Mo5 (motor trigeminal nucleus) and 7N (facial motor nucleus) accumulating various intracellular A
species (Christensen et al. 2008a). The cholinergic forebrain complex consisting of Ch1-4 showed no A
pathology, with neither extracellular A
plaque deposition, nor intracellular accumulation of A
peptides. These fibers from this region displayed swollen ChAT-positive dystrophic neurites surrounding A
plaques in the cortex and hippocampal formation. Another neuropathological alteration is the inflammatory processes, such as microglial activation and astrocyte reactivity, that occurs early during the course of the disease (Eikelenboom et al. 2006). At the age of 6 months, the APPSL/PS-1 KI mouse model upregulates different astro- and microglia markers in both brain and spinal cord including GFAP, cathepsin D, members of Toll-like receptors family, TGF
-1 and osteopontin (Casas et al. 2004; Damjanac et al. 2007; Wirths et al. 2008a). Another interesting feature is the occurrence of ganglioside alterations and an accumulation of ceramide species in the cerebral cortex of APPSL/PS1 KI mice as it was shown in human AD brain (Barrier et al. 2007; Barrier et al. 2008). As early as 3-months, these lipid alterations were increased and could be linked to the massive neuronal death observed at 6-months (Table 1). 1.2.2.3. APP/BACE mice The type I transmembrane aspartyl proteinase
-site APP cleaving enzyme (BACE1) was identified as the major
-secretase for generation of A
peptides by neurons (Luo et al. 2003). BACE cleaves APP at Asp1 and Glu11, whereas subsequent cleavage by -secretase gives rise to the A
(1-40/42) and A
(11-40/42) amyloid peptides. Deficiency of BACE1 in a double transgenic combination with human mutant APP rescued the early hippocampal

memory deficits and correlated with dramatic reduction in A levels (Ohno et al. 2004). On the other hand, mice overexpressing BACE1 in addition to human wild type (WT), APP or mutant APP increased the amyloidogenic processing of APP as revealed by increased levels of the APP metabolites sAPP, -CTF and A peptides (Willem et al. 2004). No CAA was observed probably due to the higher rate of self-association and fibrillogenic capacity of the shorter and less soluble N-truncated A11-42 peptides that form amyloid deposits in the parenchyma, indicating that BACE1 is in tight control of the balance in amyloid pathology in brain, promoting either parenchyma or vasculature. 1.2.2.4. APP/ApoE mice In epidemiological investigations, it has been found that the ApoE4 allele is genetically associated with sporadic AD with a frequency of 45% compared with 15% in the general population (Corder et al. 1993). The pathological contributions of ApoE to amyloid and tau pathology in AD have been studied in different types of transgenic mice, deficient in endogenous murine ApoE and/or overexpressed different ApoE isoforms, including various combinations with mutant human APP and PS-1 (Holtzman 2004). ApoE knockout mice have decreased significantly synaptophysin and MAP 2 staining, supporting the role of ApoE in the maintenance of synapses and dendrites during aging (Masliah et al. 1995). The finding that ApoE deficiency delayed amyloid plaque deposition in mice, while overexpression of human ApoE4 and not ApoE3 by transferring gene promoter accelerated plaque formation in transgenic mice, suggested a gain of function of ApoE4 (Bales et al. 1999; Carter et al. 2001). Authors showed that ApoE4 did not change the balance of amyloidogenic to nonamyloidogenic pathways. Nevertheless, the levels of A42 and A40 increased by ApoE4 overexpression, indicating that ApoE4 acted downstream of the production of amyloid peptides, i.e. slowed down the degradation and clearance of A peptides (Van Dooren et al. 2006). Furthermore, the neuron-specific proteolysis of ApoE4 was linked to increased phosphorylation of tau in the brain of ApoE mice (Brecht et al. 2004). Another most interesting finding is the development of CAA in cortex, hippocampus and thalamus of APP/ApoE4 and APP/ApoE4/PS-1 mice (Fryer et al. 2003). 1.2.2.5. APP/ADAM mice The endoproteolysis of APP within the A sequence by the
-secretase can preclude the formation of any A peptides. In addition, cleavage by
-secretase releases the N-terminal soluble ectodomain of APP, known as APP
, which has been claimed to exert neurotrophic and neuroprotective properties (Mattson 1997). Proteinases belonging to ADAM family (A

Desintegrin and Metalloproteinases) were the main candidates as physiologically relevant
secretases. ADAM10 and ADAM17 single knockouts have been shown to be lethal embryonically, whereas ADAM9 knockouts are viable. Transgenic mice are developed with overexpression of ADAM10 or a dominant negative catalytically inactive ADAM10 mutant with human mutant APP in double transgenic mice. Moderate neuronal levels of ADAM10 increased the secretion of APP
concomitantly with a reduction in the production of A peptides, preventing any deposition of amyloid plaques. Long term potentiation (LTP) and cognitive deficits were also improved, suggesting a fundamental rescue of synaptic function via the increased activity of
-secretases (Postina et al. 2004). 1.2.2.6. Tau and Tau/APP mice Although mutations in tau do not lead to AD, they produce dementia such as frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17). In AD and other tauopathies, the MAP tau protein is abnormally hyperphosphorylated and is accumulated as intraneuronal tangles of PHF in cell bodies of neurons. Furthermore, the number of tangles correlate significantly with degree of dementia, more so than the amyloid plaque numbers. Tau exists in six isoforms (352-441 amino-acids) by alternative splicing of exons 2, 3 and 10, with isoforms containing either three or four C-terminal tandem microtubule-binding domain repeats and either no, one or two shorter N-terminal domains (Figure 1). Preparations of PHFs from AD brains reveal only three isoforms of tau corresponding to abnormally phosphorylated tau (Goedert et al. 1992). Pathogenic mutations in the tau gene that cause FTD and FTDP-17 either reduce the ability of tau to bind to microtubules or alter the splicing of exon 10 resulting in increased 4 repeat tau isoforms. The first transgenic tau models (ALZ7 line) expressing wild-type human tau were generated in 1995 before pathogenic tau mutations had been identified. Overexpressing the longest isoform of human tau (4 repeats) under the human Thy-1 promoter resulted in hyperphosphorylation of tau and somatodendritic localization (Gotz et al. 1995). There are no NFTs, but these mice suffered from a severe axonopathy instead, with progressive paralysis of the hindlimbs, extending to the forelimbs and age related increased impairment in the performance of tasks like beam walking and rotarod (Spittaels et al. 1999). Overexpressing wild-type human 3 repeat tau under the mouse PrP promoter also resulted in hyperphosphorylation of tau and axonopathy in the spinal cord with NFTs in the hippocampus, amygdala and entorhinal cortex, albeit at very old ages (18-20 months) (Ishihara et al. 2001). Because overexpression of wild-type human tau in mice replicated very

limited aspects of tau pathology in AD, many groups turned to the discovered pathogenic tau mutations for use in animal models. In 2000, Lewis et al. (Lewis et al. 2000) published their JNPL3 mouse model where the transgene contains the most common tau mutation (P301L) associated with FTDT-17 under the mouse PrP promoter. These mice with no amyloid pathology developed NFTs associated with astrogliosis, apoptosis in spinal cord and motor and behavioural disturbances. Before producing a bigenic APP/tau mouse model, some authors injected a synthetic A
42 into somatosensory cortex and contralateral hippocampus of P301L mice resulting in a fivefold increase in NFTs numbers in the amygdala which receives projections from both cortex and hippocampus (Gotz et al. 2001). However, A
was not capable of inducing NFTs formation in non NFTs-forming WT tau transgenic mice (Gotz et al. 2001). Crossing Tg2576 mice with JNPL3 tau mice resulted in a double transgenic mouse line showing a more than seven-fold increase in NFTs numbers at 9-11 months of age compared to JNPL3 mice. However, the presence of tau did not affect amyloid pathology (Lewis et al. 2001). To address the relationship of plaques and NFTs, Oddo et al. (Oddo et al. 2003) developed a triple transgenic mouse model named 3xTg-AD. These mice harbor mutations of APPSWE, PS1M146V KI, and tauP301L and develop senile plaques first in the cortex (around 3 months of age) that spread to the hippocampus by 6 months. Tangles develop after amyloid pathology with hippocampal origin at 12 months of age and extend to the cortex. This regional and temporal development of pathology closely mimics the development of pathology in AD. These mice also exhibit synaptic dysfunction, including LTP deficits that precede senile plaques and tangles formation (Oddo et al. 2003). In this triple transgenic model, cognitive deficits are observed while no cell loss was depicted. In vitro, many kinases can phosphorylate tau, but it is very difficult to establish the equivalent in brain in vivo and to define exactly which kinases are responsible for the phosphorylation of tau at precise amino acid residues. Two kinases that are the most likely candidates in vivo are glycogen synthase kinase-3
(GSK-3
) and cyclin-dependent kinase 5 (cdk-5). Neuronal overexpression of GSK-3
by itself reduced the brain size without any phenotypic repercussion or development of tauopathy despite increased phosphorylation of tau (Spittaels et al. 2000; Spittaels et al. 2002). Surprisingly, in the tau-4R x GSK-3
double combination, the axonopathy was practically completely rescued with elimination of axonal dilations in brain and spinal cord, reduction in axonal degeneration and muscular atrophy and the alleviation of all motor problems. The amount of tau associated with microtubules was

reduced by 50% compared to single htau-4R transgenic animals and unbound tau was phosphorylated, leading to the conclusion that hyperphosphorylation of protein tau does not cause tauopathy per se. Recently, two novel bigenic mouse models, APPL/TauP301L with amyloid and tau pathology and GSK-3
/TauP301L with tauopathy only showed remarkable parallels: aggravation of tauopathy, severe cognitive and behavioural defects in young adults before the onset of amyloid deposits or tauopathy and activated GSK-3
with pathological phospho-epitopes of tau (S396/S404, characteristic GSK-3
motif). These findings indicate that A
induces tauopathy through activation of GSK-3
(Terwel et al. 2008). In addition, cdk-5 and its activating subunit p35 or its N-truncated p25 product have been inactivated or expressed in transgenic mouse brain with various degrees of success. The expression of cdk-5 with p35 and tau-4R in triple transgenic mice has yielded no additional new insights in the problem. Then, an inducible p25 mice controlled by tetracycline displayed a dramatic neurodegeneration and neuroinflammation. A 30% decrease in brain weight was evident in a 3 months observation period after the induction of p25 at the age of 6 weeks (Muyllaert et al. 2008), (Table 2). 1.2.3. Trangenic rat models of Alzheimer’s disease Parallel to the generation of transgenic mice, several transgenic rat models have also been produced as rats are a better rodent model for studies involving neurobehavioural testing, cannulation, sampling of cerebrospinal fluid, electrophysiology, neuroimaging and cell-based transplant manipulations (Abbott 2004). The first transgenic rat line was generated by Flood et al. (Flood et al. 2007). Rats have human APPSL and human PS1M146V gene mutations and developed amyloid deposits at 9 months of age. APPSWE rat model was reported but no amyloid pathology was observed except for a low intracellular accumulation of A
(Echeverria et al. 2004). Another APPSWE rat model has been generated and produced mild, extracellular A
immunostaining and failed to develop compact, mature amyloid plaques by the age of 22 months (Folkesson et al. 2007). Recently, the model of Flood et al. (Flood et al. 2007) has been more characterized: from the age of 9 months on, this rat model of AD had amyloid deposits in both diffuse and compact forms associated with activated microglia and reactive astrocytes; 2 months before the appearance of amyloid plaques, impaired LTP was revealed on hippocampal slices, accompanied by impaired spatial learning and memory in the Morris water maze; a mild amyloid angiopathy was also described on the leptomeningeal blood vessels (Liu et al. 2008a).

1.3. Invertebrate models Species as diverse as the fly Drosophila Melanogaster, the nematode Caenorhabditis elegans and the sea lamprey Petromyzon marinus have been employed to provide new insight into the pathogenesis of AD. As we will also see in other animal models of neurodegenerative disorders, these lower species offer several advantages compared to rodent models. The sea lamprey was used to study the degenerative changes linked to tau overexpression as it presents six giant neurons in the hindbrain which resemble most large vertebrate neurons and readily accessible for manipulation (Hall et al. 1997). Flies and worms have other advantages: easy and fast to breed, cheap, no ethical limitations, powerful genetics, modifier (suppressor and enhancer) screens and drug screenings possible. These models were useful to understand the normal functions and regulation of APP, PS and tau genes. Genetic approaches could identify cellular processes that can suppress A
- or tau-dependent pathology. The fly APP homolog, APPL, does not contain the segment of APP cleaved to generate pathogenic amyloid peptides. Therefore, some authors studied the physiological functions of APP and APPL in drosophila. Both proteins were shown to function as vesicular receptors for kinesin 1, a motor mediated anterograde vesicle trafficking. Flies lacking APPL or overexpressed of WT and mutant APP have axonal transport defects and only APP overexpression increased cell death in the larval brain (Cauchi and van den Heuvel 2006). Other authors introduced FAD-linked mutations at conserved residues in Drosophila PS gene or overexpressed APP/BACE and showed an increased neurotoxicity in the fly with production of amyloid peptides (Sang and Jackson 2005). Modeling AD in the fly was also attempted by delivering transgenes encoding A
40 and A
42 peptides. Results with A
42 peptides specifically expressed in brain tissue showed a reduced longevity, locomotor deficits, impaired olfactory memory and neurodegeneration whereas A
40 flies were not affected. As for the fly, C. elegans has an APP homolog, APL-1. The RNAi knockdown results in a more severe uncoordinated phenotype and genetic deletion results in embryonic or larval lethality (Link 2005; Segalat and Neri 2003). Furthermore, a transgenic C. elegans expressing human A
has been developed and showed neurodegeneration, amyloid deposits, oxidative stress, upregulation of many stress-related genes (Wu and Luo 2005). In contrast to APP, the deletion of the worm homolog tau or the fly tau homolog does not result in any detectable phenotype, probably due to compensation by other MAPs. Authors produced transgenic Drosophila and C. elegans by introducing either the normal human tau gene or various mutant forms of human tau gene. Invertebrate animals displayed neurodegeneration, a shortened life-

span, axonal transport defects, vacuolization in the cortex of the fly, positive immunostaining for a series of NFT-specific epitopes without insoluble tau fibrils in drosophila contrary to C. elegans (Gotz et al. 2004).

1.4. Primate models 1.4.1. Spontaneous approaches Although non-human primates do not spontaneously develop AD, age-related behavioural and neurodegenerative changes occur in monkeys. Indeed, it has been shown that non-human primates of several species exhibit cerebrovascular and parenchymal A
amyloidosis but without or with paucity of tau lesions (Gearing et al. 1994; Gearing et al. 1997; Martin et al. 1991; Struble et al. 1985; Walker et al. 1990; Wisniewski et al. 1973). Significant intraneuronal tau pathology was only recently documented in an aged chimpanzee (Rosen et al. 2008). Although the lesion profile in this chimpanzee differed somewhat from that in AD, the occurrence of both tau-immunoreactive paired helical filaments and A
-amyloidosis indicates that the molecular mechanisms for the pathogenesis of the two key hallmarks of AD, namely NFTs and senile plaques, are present in aged chimpanzees. In this monkey, although age probably played a role in the pathogeny of tauopathy, additional factors are suggested to be involved since it is unusual to encounter tau-immunoreactive neurons and processes in older animals (Gearing et al. 1994). Similarly to brain pathology, it was also found that the monkeys undergo an age-related decline in several domains of cognitive function (Bartus et al. 1979; Bartus et al. 1978; Lai et al. 1995; Moore et al. 2006; Rapp 1993; Rapp 1990; Voytko 1999). However, these changes were not correlated with neuronal loss in memory-related brain regions such as the hippocampus and entorhinal cortex (Peters et al. 1996) but with extensive loss of neurons in subcortical cholinergic basal forebrain regions similar to AD (Smith et al. 1999). The validity of these spontaneous models remains, however, questionable since by contrast to patients with AD in whom severe neuronal cell loss in the hippocampus can be found, the brain of normal ageing subjects displayed almost no neuron loss in this region (West et al. 1994). It can be concluded that the neurodegenerative processes associated with normal ageing and with AD are qualitatively different and that human AD is not accelerated by ageing but is a distinct pathological process. The validity of such models is also weakened by the lack of correlation between the degree of amyloid plaque accumulation and cognitive decline in aged-monkeys (Sloane et al. 1997). Therefore, the pathological and cognitive changes observed in the aged

non-human primates emphasize their value as animal models for studies of human aging but question their relevance to the human AD. 1.4.2. Lesioning approaches Lesioned animal models are based upon the assumption that the destruction of basal forebrain cholinergic neurons by injection of a neurotoxin, such as ibotenic acid, is sufficient to reproduce some of the cognitive impairments associated with AD mainly memory and learning deficits. Indeed, pathology in the basal forebrain cholinergic neurons is a prominent feature of AD and it may be responsible for the severe memory deficits observed in these patients. Impaired learning abilities, visual discrimination and memory deficit were thus elicited following lesions of the nucleus basalis of Meynert (NBM) (Irle and Markowitsch 1987; Ridley et al. 1985; Roberts et al. 1990). In other studies however, large lesions of the NBM did not impair memory or produced only transient mild deficit in visual recognition memory (Aigner et al. 1987; Aigner et al. 1991; Voytko et al. 1994). Surprisingly a, cholinesterase inhibitor (physostigmine) produced modest improvement in performance in the control group but not in the experimental animals. Thus, no consensual conclusion is available about the behavioural and cognitive effects of basal forebrain cholinergic neurons lesions in non-human primates. However, one had to keep in mind that AD is not solely a disease of the cholinergic system. 1.4.3. Pharmacological approaches Based on evidence of modest improvements in cognitive function in patients with AD and in normal human volunteers with the augmentation of central cholinergic neurotransmission by cholinesterase inhibitors such as physostigmine and tacrine, many animal studies have investigated the effects of systemic administrations of direct or indirect cholinergic modulators. The ability of cholinesterase inhibitors to reverse cognitive impairments induced by the muscarinic antagonist scopolamine has been demonstrated in non-human primates and has been the most widely exploited approach used in preclinical animal assays to identify potential therapies for AD (Aigner and Mishkin 1986; Bartus and Johnson 1976; Fitten et al. 1988; Rupniak et al. 1991; Rupniak et al. 1989; Rupniak et al. 1997; Tang et al. 1997). Although these models have provided a framework to understand AD and to test the preclinical development of drugs to treat the cognitive symptoms, fundamental questions persist regarding the validity of measures of behavioural function in animals in terms of reflecting clinically relevant measurements of cognition.

1.5. Perspectives Several animal models of AD have been developed in species ranging from worms to primates. Although none completely recapitulate the disease process, they have proven to be useful models for neuropathological changes. As will be discussed below for all animal models of neurodegenerative diseases, there is no perfect animal model for AD. It all comes to the question that is to be answered. For instance, for screening purposes of molecules against A
aggregation, one can use an A
-injected rodent; to explore mechanisms involved in the neuronal death, animal model with amyloid and tau pathology and neuronal loss such as APPSLPS-1 KI or Tau/APP mice are perhaps better suited. However, it is important to note that amyloid plaques are probably not at the origin of the neuronal death since the active vaccination in AD patients did not rescue the cognitive impairment while amyloid plaques were suppressed or reduced in brain of AD patients (Holmes et al. 2008). Many reports underlined that the intraneuronal accumulation of A
instead of extracellular A
deposits triggers an early transient pathological event leading to neuronal loss in AD. It will be interesting to study the transcriptome of APPSLPS-1 KI from the embryonic to adult life (up 6 months where a massive neuronal loss is depicted) in order to find new genes involved in the dysfunction of cell life. Furthermore, all findings in these animal AD models open a new field of research to develop an AD animal model: researchers may undertake the biological, molecular, behavioural knowledge to associate APP/PS-1 for A
accumulation with another molecular target involved in neuronal death or cognitive deficits or NFTs and inflammatory processes induced by intracellular A
neurotoxicity.

2. PARKINSON’S DISEASE 2.1. The human disease Parkinson’s disease (PD) is the second most common neurodegenerative disorder after AD. Although PD can develop at any age, it begins most commonly in older adults, with a peak age at onset at around 60 years (von Campenhausen et al. 2005). The likelihood of developing PD increases with age, with a lifetime risk of about 2% for men and 1.3% for women (Elbaz et al. 2002). Most PD cases are sporadic, of unknown aetiology, but rare cases of monogenic mutations show that there are multiple causes for the neuronal degeneration (Fahn 2003). To date, more than seven genes are known to cause familial PD. Also, 13 genetic loci, PARK1-13, have been suggested for rare forms of the disease such as autosomal dominant and autosomal

recessive PD. The pathological hallmarks of PD are the loss of the nigrostriatal dopamine (DA) neurons and the presence of intracellular proteinacious alpha-synuclein-positive inclusions in surviving neurons termed Lewy bodies (LB) and Lewy neurites (LN). A recently proposed staging procedure of PD pathology suggests a premotor period in which typical pathological changes, LB and LN, spread from the olfactory bulb and vagus nerve to lower brainstem regions (stages 1 to 2), followed by a symptomatic period when pathological changes involve the midbrain including substantia nigra (stage 3), mesocortex (stage 4) and neocortex (stages 5 to 6) (Braak et al. 2003). When PD becomes clinically overt, tremor, rigidity, bradykinesia, and postural instability are considered to be the cardinal signs of the disease. The course of the disease is chronic and progressive, and may be considerably complicated by a wide range of motor and non-motor features, many of which contribute to increased disability as well as diminished quality of life in patients and caregivers (Schrag et al. 2000).
-synuclein is a 140-amino-acid protein that is encoded by a gene, SNCA, on chromosome 4 and that is abundantly expressed in many parts of the brain and localized mostly to presynaptic nerve terminals, mainly as an isoform of 140 amino acids. Structurally,
synuclein is composed of three domains, an N-terminal amphipathic region (residues 1-60), a central hydrophobic region known as the non -amyloid component (residues 61-95) and a Cterminal acidic region (residues 96-140). Two categories of mutations causing familiar forms of the PD are known in the SNCA gene: point mutations, leading to missense variants in the encoded protein, and whole-locus multiplications leading to severe overexpression of the wild-type protein (Cookson 2005; Moore et al. 2005; Polymeropoulos et al. 1997; Singleton et al. 2003; Spillantini and Goedert 2000). Multiplications are rare, perhaps responsible for 1% of the PD families compatible with autosomal dominant inheritance. Point mutations are exceedingly rare: Ala53Thr is found in about fifteen families of Greek ancestry; Ala30Pro and Glu46Lys are present in single families, of German and Spanish origin, respectively. Three missense mutations in
-synuclein gene (A53T, A30P and E46K) (Polymeropoulos et al. 1997; Zarranz et al. 2004), in addition to genomic triplications of a region of
-synuclein gene, are associated with autosomal dominant PD (Singleton et al. 2003).
-Synuclein has an increased propensity to aggregate due to its hydrophobic non -amyloid component domain. The presence of fibrillar
-synuclein as a major structural component of LB in PD suggests a role of aggregated
-synuclein in disease pathogenesis (Spillantini et al. 1998a). Recent

studies provide compelling evidence of non -amyloid component domain and a truncated form of
-synuclein in mediating neurodegeneration in vivo.

2.2. Rodent animal models There are both toxin and genetic animal models of PD. Many different toxins are used to generate DA degeneration. The most frequently used toxins in rodent models of PD are 6hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). 2.2.1. The 6-OHDA model 6-OHDA shares some structural similarities with DA and norepinephrine, and has a high affinity for several membrane transporters such as the DA (DAT) and norepinephrine transporters (NET) (Bezard et al. 1999; Breese and Traylor 1971; Pifl et al. 1993). 6-OHDA cannot cross the blood-brain barrier and must therefore be injected directly into the brain (Sachs and Jonsson 1975). Once inside the neurons, it is rapidly oxidized into 6-OHDAquinone and hydrogen peroxide, both of which are highly toxic (Saner and Thoenen 1971) as they inhibit the mitochondrial respiratory chain enzyme complex I and IV, thus causing neurodegeneration of DA neurons (Glinka and Youdim 1995; Ichitani et al. 1991). The extent of loss of DA neurons and their striatal terminals is dependent upon the dose of the toxin injected and the site of toxin injection. The toxin can be injected intrastriatally, into the median forebrain bundle (MFB, that comprises the nigrostriatal tract), or directly into the subsantia nigra (SN). This toxin does not produce LB-like inclusions (Dauer and Przedborski 2003). 2.2.1.1. Striatal injection 6-OHDA delivered into the striatal DA terminals has been widely used to examine neuroprotective strategies. Unilateral delivery of 6-OHDA into the striatum produces a slow and progressive retrograde degeneration of DA neurons. One major advantage of this model is that it damages only DA neurons projecting to the striatum, allowing for examination of neuroprotective strategies. In addition, because in the striatum there are no NE terminals, this allows 6-OHDA to be specific to DA neurons. One drawback, to a striatal injection to model PD is that behavioural deficits are more subtle and thus can be difficult to detect. In addition, dependent on the degree of DA depletion in the striatum, animals were reported to recover within several days, unless the lesion extends 80%. This recovery is attributed to compensatory mechanisms (increased release, decreased reuptake) of residual DA neurons

and to changes in crossed projections from the contralateral hemisphere. 2.2.1.2. Medial forebrain bundle injection 6-OHDA placed along the MFB produces a rapid degeneration of DA neurons and terminals where a loss of DA levels in the striatum can be detected by 24 hours after 6OHDA injection and a significant loss of DA neurons in the SN by 3 days post-6-OHDA. In addition to producing a large cell death to the nigrostriatal pathway, unilateral MFB injections produce reliable, long lasting behavioural deficits. A major issue regarding placement of 6-OHDA along the MFB is that of specificity. Because 6-OHDA is a catecholamine analogue and not simply an analogue of DA, when placed in the MFB, 6OHDA can produce damage to NE terminals. In order to create specific damage to only DA neurons, 6-OHDA can be used in conjunction with a NE uptake inhibitor (such as dismethylimipramine), thereby blocking entry of 6-OHDA into NE terminals. Another drawback to the MFB lesion is that it can produce (depending on dose) a rather large and rapid cell death that can sometimes overwhelm potential neuroprotective strategies that may take longer time periods to produce beneficial effects. Additionally, because of the speed with which MFB lesions produce death of DA neurons, it does not closely mimic the chronic course of the clinical condition. 2.2.1.3. Substantia nigra injection The injection of 6-OHDA in the SN destroys the DA cell bodies within a few hours and before degeneration of striatal terminals (Jeon et al. 1995). Injection of 6-OHDA to the ventral midbrain produces a nearly complete destruction of SN neurons and striatal tyrosine hydroxylase (TH)-immunoreactive terminals. Delivery of 6-OHDA into the SN appears to be a more useful approach for testing cell replacement therapies (Hirsch et al. 2003). 2.2.1.4. Behavioural impairment following 6-OHDA lesions In the unilateral 6-OHDA model, also known as “hemiparkinson model,” the intact hemisphere serves as an internal control structure (Perese et al. 1989; Schwarting and Huston 1996). Among the motor tests used following 6-OHDA lesions, the ‘gold standard’ measures the extent of a DA lesion following administration of the DA precursor, L-DOPA, or DA agonists, such as apomorphine (Ungerstedt and Arbuthnott 1970) and counting the number of rotations. Amphetamines have been termed indirect DA agonists, since they affect DA receptors indirectly by increasing the extracellular availability of endogenous striatal DA (Jones et al. 1998). Amphetamine treatment can induce ipsilateral rotations, the direction of

turning is attributed to the release of DA in the unlesioned hemisphere. Apomorphine is a DA receptor agonist which stimulates both classes of DA receptors (D1, D2). Apomorphine treatment can induce contralateral rotations; the direction of turning is attributed to the stimulation of supersensitive D1-receptor and D2-receptor, especially in the lesioned hemisphere. This approach allows easily the control of the extent of DA lesion and evaluates the power of therapeutic treatments, a major advantage of the 6-OHDA model of PD (Beal 2001). The other deficit in 6-OHDA lesioned animals model is sensory neglect to visual, tactile or olfactory stimuli that can be evaluated as the thresholds for leg withdrawal to footshocks. This behavior is believed to be due to damage in the lateral hypothalamus through which the ascending fibers of mesencephalic DA neurons pass. In addition, many researchers use the forepaw usage deficit contralateral to the side of the lesion as a method to evaluate the behavioral consequences of 6-OHDA et the potential efficiency of neuroprotective agents or cell transplantation strategies. Contralateral deficits with massive lesions were also observed in the “stair-case”-test, where the rat has to reach downwards for food with either only the left or the right paw. Behavioral asymmetries following unilateral 6-HAD lesions were were also found in swimming rats tested in circular pools (for a complete review on this issue see (Schwarting and Huston 1996). In summary, the 6-OHDA model does not mimic all pathological and clinical features of human parkinsonism. It induces DA neuron death, whereas the formation of cytoplasmatic inclusions (LB) does not occur. However, these models are very useful for testing cell replacement therapies or neuroprotective treatments. 2.2.2. The MPTP model It is in the late 70s that a by-product of a synthetic drug, the MPTP, has been identified as a cause of parkinsonism in drug addicts (Langston et al. 1983). The subsequent identification of MPTP as a dopaminergic toxin led to it becoming the most widely used toxins to mimic the clinical and pathological hallmarks of PD. MPTP is highly lipophilic and readily crosses the blood-brain barrier. After administration, MPTP is metabolized in astrocytes to its active metabolite 1-methyl-4-phenylpyridinium (MPP+) by the monoamine oxidase B (MAO B), an enzyme involved in monoamine degradation (Nicklas et al. 1985; Przedborski and Vila 2003). MPP+ is selectively taken up by the DAT and is accumulated in mitochondria where it inhibits complex I of the electron transport chain (Langston et al. 1984b; Mizuno et al. 1987; Nicklas et al. 1985). This reduces ATP production and causes an

increase in free-radical production. Dopaminergic neurons in SNc are particularly vulnerable to the action of MPTP (Giovanni et al. 1991). In rodents, MPTP is systemically administrated, either intraperitonealy or subcutaneously, and with repeated injections. There are marked species differences in susceptibility to the neurotoxic effects of MPTP. For instance, rats are resistant to MPTP toxicity as their catecholamine neurons seem to better cope with, and survive, impaired energy metabolism. Mice strains vary widely in heir sensitivity to the toxin. When administered with multiple high MPTP doses, exhibit striatal DA reductions, SN neuron loss and behavioural impairment (Heikkila et al. 1984). However, depending on the endpoint tested, MPTP effects in mice vary with dose, route, number and timing of injections, as well as gender, age (Jarvis and Wagner 1985) and strain (Tipton and Singer 1993). The MPP+, the toxic metabolite of MPTP can also be used to obtain animal model of PD. Systemic administration of MPP+ does not damage central DA neurons, because it does not readily cross the blood-brain barrier due to its charge. However, its direct injection into the brain effectively destroys much of the DA nigrostriatal pathway. The rotarod and open field locomotion tests are used to evaluate the motor deficits following MPTP treatments. These tests are only effective if they are employed shortly after treatment when the mice are still intoxicated by MPTP. Mice tested later show no deficit on the rotarod (Meredith and Kang 2006). More sensitive measures, such as gait analysis, or the pole or grid tests, have been able to detect DA loss as low as 50% (Meredith and Kang 2006). However, motor deficits do not correlate well with the extent of DA neuronal loss, striatal DA levels or the dose of MPTP (Rousselet et al. 2003). Today, MPTP represents the most important and most frequently used parkinsonian toxin applied in animal models (Beal 2001; Przedborski et al. 2001). The major advantage of the MPTP is that, it causes directly a specific intoxication of dopaminergic structures and it induces in humans symptoms virtually identical to PD (Przedborski and Vila 2003). The major drawback of MPTP is that the cell loss is strain, age and gender dependent in mice (Smeyne et al. 2005; Sundstrom et al. 1987). 2.2.3. Genetic rodent models of PD PD is generally a sporadic disorder, but in a significant proportion of cases (10–15% in most studies) it runs in families without a clear cut Mendelian pattern. Currently, there have been 13 defined loci identified to be associated with high penetrant autosomal dominant or

recessive PD, of which causative mutations in specific genes have been identified. These genes include
-synuclein, parkin, ubiquitin carboxyl-terminal esterase L1 (UCH-L1), PTENinduced putative kinase 1 (PINK1), DJ-1 and Leucine-rich repeat kinase 2 (LRRK2). As outlined in Table 3, most of these mutations can be characterized by an early onset of disease. 2.2.3.1. PD caused by mutations in the
-synuclein gene (PARK1) Overexpression of
-synuclein lacking residues 71–82 failed to aggregate and form oligomeric species in drosophila model of the disorder resulting in an absence of dopaminergic pathology as no loss of tyrosine hydroxylase-positive neurons was observed. The expression of a truncated form of
-synuclein showed an enhanced ability to aggregate into large inclusions bodies, an increased accumulation of high molecular weight alphasynuclein species, and an enhanced neurotoxicity in vivo (Periquet et al. 2007). To investigate the function of
-synuclein in mice, several transgenic mice lacking
-synuclein or expressing either WT or mutated (A30P, A53T, or both) human
-synuclein were generated. The first line of
-synuclein knockout mice display a reduced level of DA in the striatum (Abeliovich et al. 2000) however, behavioral assessment did not reveal any major impairment. The second line of
-synuclein null mice generated by Dauer et al. (Dauer et al. 2002) were completely resistant to MPTP intoxication, likely due to an incapacity of MPP+ to inhibit complex I in these mice. A third line of
-synuclein knockout mice generated showed a partial protection to MPTP-induced striatal DA loss and an increased methamphetamineinduced DA depletion (Schluter et al. 2003). Expression of truncated
-synuclein under the TH promoter led to nigrostriatal pathology (Tofaris et al. 2006). Expression of amino acids 1–130 of the human protein with the A53T mutation caused embryonic loss of DA neurons in the SN whereas expression of the fulllength protein did not (Wakamatsu et al. 2008). Expression of amino acids 1–120 of the wildtype human protein on a
-synuclein null background only led to decreased striatal DA without loss of DA neurons in SN (Tofaris et al. 2006). Although several
-synuclein null mice and transgenic overexpression mutations have been created, none exhibited consistent neuronal degeneration of DA terminals. 2.2.3.2. PD caused by mutations in the parkin gene (PARK2) The parkin gene, which mapped to chromosome 6, encodes a 465 amino acid protein containing an N-terminal ubiquitin-like domain, a central linker region and C-terminal RING domain. The parkin protein functions as an E3 ubiquitin protein ligase, and is involved in the

degradation of cellular proteins by the proteasomal pathway. The loss of parkin’s E3 ligase activity due to mutations leads to autosomal recessive juvenile PD (Kitada et al. 1998; Shimura et al. 2000; Zhang et al. 2000). Mutations in parkin were first identified in 1998, in Japanese patients with autosomal recessive juvenile parkinsonism (Kitada et al. 1998). About 50% of the mutations found in parkin are point mutations. The remaining 50% consist of genomic rearrangements. By targeting different exons of the parkin gene, several parkin knockout mice were generated. In mice, exon 3 deletion did not affect the number of nigral DA neurons. However, the mice exhibited behavioural deficits that are associated with the basal ganglia function and have decreased DA release in response to amphetamine (Goldberg et al. 2003). Similar to exon 3 deletion, exon 7 deletion did not affect the nigral neuron numbers, but decreased TH-producing cells in the locus coeruleus (Von Coelln et al. 2004). Mice with a knockout of exon 2 exhibited age related declines in striatal DA and increase in D1/D2 receptor binding. Behavioural testing and immuno-labeling of dopaminergic nigral neurons revealed no abnormalities compared to WT mice (Sato et al. 2006). Overall, parkin knockout mice fail to develop a Parkinsonian phenotype, but the different knockout models generated may provide means to examine the role of parkin in protein turnover, oxidative stress and mitochondrial dysfunction. 2.2.3.3. PTEN-induced kinase-1 (PINK1) mutations The protein PTEN-induced putative kinase 1 (PINK1) was identified to be gene associated with the PARK6 locus on chromosome 1p36 that is linked to a rare familial form of PD (Valente et al. 2004). Mutations in the PINK1 are a common cause of autosomal recessive PD (Hatano et al. 2004). PINK1 contains 8 exons and encodes a protein of 581 amino acids with a mitochondrial targeting motif and a serine-threonine protein kinase domain. Most of reported mutations were distributed throughout the serine-threonine protein kinase domain. Thus, loss of function of kinase activity of PINK1 is the most probable disease mechanism (Silvestri et al. 2005; Valente et al. 2004). To date, no mammalian in vivo studies of PINK1 loss-of-function have been reported. However, PINK1 loss-of-function mutants in Drosophila results in mitochondrial morphological defects in the male germline, muscle and DA neurons as well as reduced ATP content (Park et al. 2006). These phenotypic effects were attributed to severe mitochondrial dysfunction such as enlargement and fragmentation of christae. 2.2.2.4. DJ-1 (PARK7) mutations The PARK7 locus, localized on chromosome 1p36, has been linked with autosomal recessive

early-onset PD. Recent studies have identified mutations in the DJ-1 gene, associated with the PARK7 locus (Bonifati et al. 2003). The first mutations described were a large chromosomal deletion in a Dutch family and a L166P point mutation in an Italian family (Bonifati et al. 2003). DJ-1 is a highly conserved and ubiquitous protein that is widely expressed in both neurons and glia (Bader et al. 2005). DJ-1 knockout mice show motor impairments and nigrostriatal DA dysfunction associated with reduced DA overflow, resulting in increased reuptake of DA by the DAT (Chen et al. 2005; Goldberg et al. 2005). In agreement with the observations that DJ-1 knockout mice have enhanced DA reuptake capacity, DJ-1 knockout mice have enhanced sensitivity to MPTP, which led to increased striatal DA denervation (Kim et al. 2005; Manning-Bog et al. 2007). However, DJ-1 knockout mice lack SN degeneration, suggesting that loss of DJ-1 function might confer increased susceptibility to parkinsonism as a result of underlying SN dysfunction. 2.2.2.5. LRRK2/dardarin mutations Genome wide linkage analysis of a Japanese family with autosomal dominant PD identified a linkage with a genetic locus located on chromosome 12, which has been termed PARK8 (Funayama et al. 2002). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene (the protein has been named dardarin) have been identified in families with autosomal dominant late onset PD (Paisan-Ruiz et al. 2004; Zimprich et al. 2004a; Zimprich et al. 2004b). The neuropathology associated with LRRK2 mutation consists of nigral neuronal degeneration and gliosis but with variable intraneuronal protein inclusions including LB, tau-positive NFTs, ubiquitin-positive intranuclear and cytoplasmic inclusions or the absence of distinctive inclusions/aggregates (Funayama et al. 2002; Giasson et al. 2006; Khan et al. 2005; Rajput et al. 2006; Ross et al. 2006; Wszolek et al. 2004). These observations have led to the suggestion that LRRK2 could be a critical central regulator of protein aggregation and deposition relevant to a wide array of neurodegenerative disorders (Taylor et al. 2006). Within the nigrostriatal pathway, LRRK2 is localized at high levels to medium-sized spiny output projection neurons, cholinergic interneurons and various GABAergic interneuronal subtypes in the caudate putamen, but at markedly lower levels in DA neurons of the SNc (Biskup et al. 2006; Higashi et al. 2007a; Higashi et al. 2007b). Drosophila LRRK2 mutants displayed reduced female fertility and fecundity, impaired locomotor activity and a progressive reduction in TH immunostaining and aberrant morphology in certain DA clusters despite normal numbers of DA neurons (Lee et al. 2007). These results suggest that LRRK2 is critical for the integrity of dopaminergic neurons and intact locomotive activity in

Drosophila.

2.3. Non-human primate models Initial primate models were developed by using toxins that specifically targeted DA neurons, the most successful of which is MPTP (Langston et al. 1984a). In monkeys, MPTP produces an irreversible and severe parkinsonian syndrome characterized by all of the features of PD, including tremor, rigidity, slowness of movement, postural instability, and freezing. In these animals, the beneficial response to levodopa and development of long-term motor complications to medical therapy, namely dyskinesias, are virtually identical to that seen in PD patients (Bezard et al. 2001; Jenner 2003; Langston et al. 1984a). The findings that the MPTP non-human primate exhibit cognitive deficits and autonomic disturbances comparable to patients with PD (Goldstein et al. 2003; Schneider and Pope-Coleman 1995) bring this model closer to the idiopathic PD. Mutations in the
-synuclein gene have been shown to cause familiar PD, suggesting that abnormal accumulation of
-synuclein may trigger the neurodegeneration (Polymeropoulos et al. 1997). As one of the limitations of the MPTP non-human primate model of PD is the absence of the progressive development of the
-synuclein pathology that is the hallmark of idiopathic PD, attempts to over express
-synuclein was recently achieved in non-human primates. Indeed, unilateral injection of human
-synuclein expressing viral vectors into the SN of adult marmosets caused selective loss of DA neurons accompanied by
-synucleinpositive cytoplasmic inclusions and degenerative changes in TH-positive axons and dendrites as well as motor impairment reminiscent of DA denervation (Kirik et al. 2003). This model did not however display the wider clinical parkinsonian repertoire that can be elicited in the MPTP-lesioned monkey and was not challenged with levodopa to test the reversibility of its motor impairment. Besides of valuably complementing the existing non-human primate models, this approach will pave the way for the refining of new therapeutic strategies.

3. MULTIPLE SYSTEM ATROPHY 3.1. The human disease Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of unknown etiology characterized by autonomic failure and motor impairment resulting from levodopa unresponsive parkinsonism, cerebellar ataxia and pyramidal signs. Eighty percent of cases

show predominant parkinsonism (MSA-P) due to underlying striatonigral degeneration (SND), and the remaining 20% develop predominant cerebellar ataxia (MSA-C) associated with olivopontocerebellar atrophy (Wenning et al. 2004). These features result from progressive multisystem neuronal loss that is associated with oligodendroglial
-synuclein inclusions (Lantos 1998). There is a lack of effective therapies particularly for the motor features of MSA. Most patients deteriorate rapidly and survival beyond ten years after disease onset is unusual. MSA is less common than PD as epidemiological studies estimate a prevalence of 1.9-4.9 people per 100 000 (Chrysostome et al. 2004; Schrag et al. 1999). Histopathologically, there is variable neuron loss in the striatum, SNc, cerebellum, pons, inferior olives and intermediolateral column of the spinal cord. Glial pathology includes astrogliosis, microglial activation and argyrophilic oligodendroglial cytoplasmic inclusions (GCIs) (Papp et al. 1989). In MSA brains,
-synuclein aggregates in the cytoplasm, axons and nuclei of neurons, and in the nuclei of oligodendroglia (Benarroch 2002; Fearnley and Lees 1990; Lantos 1998; Wenning et al. 1997). Thus, in contrast to neuronal
-synuclein inclusions in PD, MSA is also characterized by oligodendroglial
-synuclein inclusion pathology, suggesting a unique but poorly understood pathogenic mechanism that could ultimately lead to neuron loss via disturbance of axonal function (Wenning et al. 2008).

3.2. Rodent animal models As the major, although not the only, histopathological feature of MSA-P is nigral and striatal degeneration, the most evident and direct approach to generate animal models of this disease is with double nigral and striatal lesions using specific toxins. This can be achieved by either stereotaxic or systemic lesions. Stereotaxic lesions are essentially performed unilaterally to obtain impairment in paw reaching behaviour and a rotational behaviour induced by either amphetamine or the DA receptor agonist apomorphine. In this case, SNc lesion is done simultaneously or before striatal lesion. For this, DA neurons within the SNc can be stereotaxically lesioned with 6-OHDA applied within the striatum or the MFB. Striatal lesion is usually obtained by stereotaxical injection within the striatum of quinolinic acid (QA). QA is a tryptophan metabolite and a glutamate NMDA agonist with potent excitotoxic effects. Once injected into the striatum QA preferentially induces loss of medium spiny GABAergic neurons, that constitute 90% of the striatal neurons, while sparing most of the remaining interneurons (Figueredo-Cardenas et al. 1998; Foster et al. 1983; Ghorayeb et al. 2001; Stone 1993). This model was first developed by the group of Wenning et al. (Wenning et al. 1996)

that administered 6-OHDA into the left MFB of male Wistar rats, followed 3-4 weeks later by intrastriatal injection of QA into the ipsilateral striatum. The model was used to test the potential efficiency of striatal fetal allografts derived from striatal primordium alone or combined with cografts of ventral mesencephalon. They showed that cografted rats have a reduction in amphetamine-induced rotation but do not improve deficits of more complex behavior. These stereotaxic unilateral double lesion approaches were instrumental in evaluating neuroprotection efficiency and transplantation strategies but they bare several drawbacks as they are invasive, with immediate histological consequences, as opposed to the progressive nature of the disease, and they do not mimic the clinical symptoms observed in the human pathology. Some of these limitations may be circumvented with systemic lesions that have also been extensively performed to produce animal models of this disorder and that provide a more dynamic approach of the neurodegenerative process and the subsequent behavioural consequences (Fernagut et al. 2004; Stefanova et al. 2003). In these approaches, DA neurons are degenerated following MPTP systemic injection that induces PD-like syndromes in several species including mice and primates (Burns et al. 1983). Selective damage of the striatum is obtained with 3-nitropropionic acid (3-NP), a mycotoxin inhibitor of succinate dehydrogenase (SDH) in most species Przedborski (Alexi et al. 1998; Brouillet et al. 1999) and thus that induces metabolic failure by inhibiting mitochondrial respiration (Alexi et al. 1998; Brouillet et al. 1999; Brouillet and Hantraye 1995; Guyot et al. 1997; Ludolph et al. 1991). The susceptibility, nature (apoptotic or necrotic) and extent of the striatal damage depend upon the species, animal strain, age, dose administered and administration schedule (acute versus chronic) (Alexi et al. 1998; Ouary et al. 2000; Pang and Geddes 1997). In mice, 3-NP produces an acute early oxidative stress followed by an apoptotic striatal neuronal death in the following days (Kim and Chan 2001). Mice lesioned with this protocol developed severe and long-lasting motor disorders as assessed with rotarod, pole test and general locomotor activity measures. Striatal and nigral damage were also evident with significant neuronal loss and astroglial activation (Fernagut et al. 2004). In general, these double lesion approaches are considered by many to be too simplistic as they fail to closely model the MSA pathology. For instance, the lesional approach does not induce GCIs inclusions, one of the hallmarks of MSA that is believed to be involved in neurodegeneration (Papp et al. 1989). In this line, the discovery that GCIs contain a significant level of
-synuclein (Spillantini et al. 1998b; Wakabayashi et al. 1998) has lead to

the development of transgenic animal models over expressing this protein under the control of the proteolipid-protein (Kahle et al. 2002) or the 20,30-cyclic nucleotide 30phosphodiesterase promoter (Yazawa et al. 2005). However, none of the generated mice showed a major degeneration in the nigrostriatal pathway although some showed a moderate loss of nigral DA neurons. Another drawback to the use of the double lesions models is that neurotoxins can interact together, rendering difficult to control and replicate the extend of lesion. To overcome these interactions, a model striatonigral degeneration which uses a single unilateral administration of 1-methyl-4-phenylpyridinium ion (MPP+) into the rat striatum has been developed (Ghorayeb et al. 2002). This resulted in both nigral and striatal degeneration and motor

behaviour impairements in relation to this double degeneration. Researchers applied also 3-NP to
-synuclein transgenic animals hoping to induce striatal degeneration as well. These lesioned transgenic mice, showed severe loss of nigral and striatal neurons in addition to astrogliosis and microglial activation reminiscent of the pathology of MSA and thus are considered to be closer to the human disease; they are currently used to test the efficiency of neuroprotective agents (Stefanova et al. 2008). The fortuitous discovery that transgenic mice over-expressing the
1B-adrenergic receptor bear several features with MSA, speared curiosity among researchers, as implication of the NE transmission in the pathogenesis of MSA was never previously suspected (Zuscik et al. 2000). Although the group that has developed these mice do acknowledge that MSA is not due to a mutated form of this receptor, this transgenic model may nevertheless be useful in dissecting the neurotransmission pathway that might be implicated in this disease. Transgenic mice for this receptor show prominent cerebellum and medulla neurodegeneration as well as moderate to significant degeneration in the basal ganglia, periaqueducal gray, spinal cord, thalamus and cerebral cortex. Brain regions showed positive staining for ubiquitin and
synuclein, two proteins typically found in inclusion bodies, and capspase 3 expression was documented in the white matter tracts of the striatum and cerebellum. Behaviourally, these transgenic mice had reproductive problems, reduced weight and reduced locomotor activity that was age related. In addition, these mice show increased seizures with age and a generalized pattern of brain damage not found in MSA.

3.3. Primate animal models

The first effort to model SND as the core neuropathology underlying MSA-P in non-human primates was based on the use of selective nigral and striatal neurotoxins, as previously performed to mimic PD and Huntington’s disease in monkeys (Brouillet et al. 1999; Langston et al. 1984a). Systemic and sequential chronic administration of the mitochondrial inhibitor 3NP and MPTP in one non-human primate reproduced levodopa-unresponsive parkinsonism and SND-like pathologic changes characteristic of MSA-P (Ghorayeb et al. 2000). Indeed, the administration of MPTP induced a marked levodopa-sensitive parkinsonian syndrome associated with akinesia, bilateral rigidity, and flexed posture as well as tremor episodes. The subsequent chronic intoxication with 3-NP resulted in a progressive further deterioration of the motor status, and, after the appearance of lower limb dystonia and an abrupt aggravation of parkinsonism, the dopaminergic responsiveness disappeared except for levodopa-induced orofacial dyskinesias. Histopathologically, this sequential intoxication produced a severe degeneration of the SNc and of the dorsolateral putamen and head of the caudate nucleus comparable with that found in MSA-P. Although, this double-lesion primate model of SND may serve as a preclinical test-bed for the evaluation of novel therapeutic strategies in MSAP, its reliability and validity were not tested furthermore.

4. AMYOTROPHIC LATERAL SCLEROSIS 4.1. The human disease Amyotrophic lateral sclerosis (ALS) is one of the major forms of motor neuron disease (MND), a heterogeneous group of degenerative disorders causing progressive motor neuron death leading to paralysis and death. Amyotrophic lateral sclerosis is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year (Logroscino et al. 2008). This fatal disease results from the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The pathogenesis of MND is poorly understood and may include genetic and/or environmental factors, with a common end-stage outcome. There are currently no significant treatments to alter the fatal outcome. About 10% of ALS cases are familial (FALS), with a Mendelian pattern of inheritance. About 20% of these cases are associated with mutations in the copper/zinc superoxide dismutase 1 gene (SOD1) (Valdmanis and Rouleau 2008). To date, more than 100 different mutations within all exons of the SOD1 gene and its introns have been identified as being involved in the development of chromosome 21q-linked FALS. The remaining 90% of ALS cases are

classified as sporadic (SALS), although there is accumulating evidence that subpopulations of patients with SALS have common inherited susceptibility genes (Greenway et al. 2006). In SALS, degeneration of the corticospinal tracts in the anterior and lateral columns of the spinal cord is particularly evident. The cytopathology of the affected motor neurons in SALS is characterized by the following two important intracytoplasmic inclusions: the Bunina bodies, which are small eosinophilic intraneuronal inclusions in the remaining lower motor neurons, are generally considered to be a specific pathologic hallmark of ALS. Although the nature and significance of Bunina bodies in ALS are not yet clear, the bodies may be abnormal accumulations of unknown proteinous materials (Okamoto et al. 2008). Skeins-like inclusions (SLIs) and round hyaline inclusions (RHIs) in the remaining anterior horn cells are another pathologic characteristic finding of ALS. Both inclusions are detected by ubiquitin immunohistochemistry but are negative for phosphorylated neurofilament protein and SOD1. In FALS, two types can be discriminated by histopathology. One type of FALS is neuropathologically identical to SALS, and frequently contains Bunina bodies. The other form of FALS is that showing posterior column involvement in addition to the pathological features of SALS (Valdmanis and Rouleau 2008). Neuropathologically, this entity is characterized by the presence of LB-like hyaline inclusions (LBHIs) in the anterior horn cells throughout the spinal cord. It is to be noted that many SOD1-mutated FALS cases are of the posterior column involvement type with neuronal LBHIs and mild corticospinal tract involvement, in contrast to severe degeneration of the lower motor neurons (Kato 2008).

4.2. Animal models Several rodent animal models of ALS have been generated targeting a set of proteins ranging from the SOD1 gene to genes causing neurofilament abnormalities or defects in microtubulebased transport (Cozzolino et al. 2008; Julien and Kriz 2006; Kato 2008). To date, SOD1 mutants are widely considered as the closest mutants to the human pathology despite the fact that it is still debated how mutations in SOD1 gene may lead to ALS syndromes. In this line, an impressive number of SOD1 transgenic rodents expressing various SOD1 mutations have been generated, most replicating rather efficiently many behavioural and anatomical features of ALS. Since the pathology is believed to be de due to a gain of function following SOD1 mutation, the main difference in these different lines seems to be the number of copies of SOD1 mRNA expressed. Indeed, the toxicity of SOD1 mutation does not seem to be related

to a decreased enzymatic activity as some mutants show actually an increased activity while Knock-out animals for SOD1 show almost no motor neuron death (Reaume et al. 1996). Studies on transgenic mice expressing various SOD1 mutants have generated a wealth of information. Although no clear picture can de brawn, it is now admitted that multiple cascades of events are involved in motor neuron death that are independent of the enzymatic activity involving the copper catalytic site but related to the aggregation of misfolded mutant SOD1 (Chou et al. 1998; Hyun et al. 2003; Jonsson et al. 2004; Takamiya et al. 2003). How this is related to the events leading to neuron death is yet to be determined especially given the wide variety of biochemical alterations ranging from excitotoxicity through alerted glutamate transmission, oxidative damage, defects in calcium homeostatsis, capspase activation, mitochondrial malfunction and cytoskeleton alterations (Guegan et al. 2001; Howland et al. 2002; Liu et al. 2004; Swerdlow et al. 1998; Van Den Bosch et al. 2006). The level of expression of SOD1 seem to be proportional to the life span of the animals, i.e. the more copies they express, the shorter they live, with some animals having up to 40 times increase in the mRNA levels of SOD1 (Jonsson et al. 2006). A caveat of this approach is that one can question the validity of such models since high levels of SOD1 protein can produce histopathological artefacts such as the formation of vacuoles. Another factor that should be considered regarding the SOD1 protein is its stability and degradation rate especially in the spinal cord so that even with low levels of protein some mutants show significant motor neuron loss (Sato et al. 2005). This further comforts the protein aggregation hypothesis as a key element in the histopathology of the disease. Most of the SOD-1 transgenic mice express motor deficits that start with a mild tremor followed by atrophy of hind limbs muscles ultimately leading to a complete paralysis where mice can no longer sustain themselves and are thus sacrificed. The early histopathological feature in SOD1 transgenic mice is formation of perikarya, axonal, and dendritic vacuoles (Wong et al. 1995) that appear before neuronal loss and astrocytosis as early as 4-6 weeks of age in the G93A mice where glycine is substituted to alanine at position 93 (Zhang et al. 1997). At this time point, mice are still asymptomatic as the first symptoms appear at three months of age when loss of large motor neurons is observed in the spinal cord with massive vacuolization. At 5 months of age, mice are paralysed most probably due the substantial loss of motor neurons accompanied by marked gliosis, intracellular inclusions reminiscent of LB and phosphorylated neurofilaments filling few motor neurons (for a review of cell death features in ALS see (Cleveland 1999).

Non-neuronal abnormalities are also thought to be involved in the ALS (Bruijn et al. 1997; Howland et al. 2002; Lin et al. 1998; Nagai et al. 2007; Rothstein et al. 1995). For instance, altered reuptake of glutamate by astrocytes through glutamate transporter EAAT2 was observed in mice or rats expressing mutant SOD1 (Vermeiren et al. 2006). This should lead to increased extracellular glutamate and thus substantial activation of glutamate receptors and subsequent increase in intracellular Ca++ homeostasis. Increased cytokine levels indicating inflammatory process through microglial activation were also reported in transgenic SOD1 mutant mice (Hensley and Floyd 2002) and in human tissues (Henkel et al. 2004) suggesting that motor neuron degeneration implicate inflammation processes. As mentioned above, motor neurons of ALS patients contain spheroids that are axonal inclusion bodies essentially composed of intermediate filaments. Neurofilament and peripherin mutations were reported in rare forms of ALS (Gros-Louis et al. 2004; Leung et al. 2004) leading researchers to develop animal models bearing these mutations (Millecamps et al. 2006). Although these mice developed no evident MND, some exhibited moderate sensorimotor and spatial deficits probably due to the observed reduction in conduction velocity. Patients with an autosomal recessive form of juvenile ALS show deletion mutations in ALS2 gene coding for Alsin, a protein that seems to be involved in Ras transduction pathway (Yang et al. 2001). ALS2 knock-out mice however show mild behavioural abnormalities especially in motor coordination accompanied by discrete and age related loss of cerebellar Purkinke cells (Cai et al. 2008). Presently, is no currently available non-human primate model of ALS. Transgenic rodent models that exhibit many of the pathological changes in human ALS provide useful tools for drug testing and essays of genetic manipulations as no effective treatment for ALS has yet been found. Animal models with lower gene copy number encoding the mutant SOD1 proteins and with slower and later onset of disease may prove more appropriate to the human pathology. In addition, one might also question the validity of the mutant SOD1 mice as models of gene defects that account for only 2% of ALS cases.

5. HUNTINGTON DISEASE 5.1.The human disease Huntington's disease (HD) is an inherited autosomal dominant progressive neurodegenerative disease that is diagnosed commonly at the age of 35-50 years. Typically, onset of symptoms

is in middle-age, but the disorder can manifest at any time between infancy and senescence. Its prevalence in North America and Europe varies between 0.5 and 10/100,000; it is highest in populations of western European origin and lowest in African and Asian populations (Harper 1992). The underlying genetic cause is an expanded trinucleotide CAG repeat of more than 36 units in the IT15 (for “interesting transcript”) gene encoding the huntingtin (HTT) protein in chromosome 4 (1993). This will lead to the production of mutant HTT protein with an abnormally long polyglutamine residue (polyQ). The disease occurs when the critical threshold of about 37 polyQ is exceeded. One important characteristic of HD pathology is the vulnerability of a particular brain region, the caudate–putamen, despite similar expression of the mutated HTT protein with expanded polyQ in other brain areas. The ensuing degeneration with atrophy, neuronal loss and gliosis, initially involves the striatum then the cerebral cortex, and eventually degeneration may appear throughout the brain as a constellation of the toxic effect of the mutation and the ensuing secondary changes (Albin 1995; Vonsattel et al. 2008). Interestingly, not all striatal cells are equally affected by the degenerative process. Immunocytochemical studies combined with neuro-chemical analysis have consistently shown that HD preferentially affects the GABAergic medium-sized spiny neurons, leaving the other subpopulations of striatal cells largely unaffected, at least in the early course of the disease (Cicchetti et al. 1996). Given that these neurons constitute up to 90% of the striatal neurons in total, the consequences of this degeneration are devastating (Jaber et al. 1996). The actual causative pathway from the HD gene mutation to neuronal dysfunction and loss has not yet been established but two pathogenic processes have been suggested as the basis for neurodegeneration in HD. One process involves interaction of mutant HTT with other proteins to confer a toxic gain of function. Alternatively, mutant HTT might homodimerize or heterodimerize to build a poorly soluble HTT protein that aggregates within ubiquitinated neuronal intranuclear inclusions and dystrophic neuritis in the HD cortex and striatum (DiFiglia et al. 1997). Clinically, HD is increasingly recognized as a phenotypically heterogeneous disorder. Its motor features can be conceptually divided into positive and negative. Positive motor features are those characterized by excessive movement, such as chorea and dystonia; conversely, negative motor signs describe a poverty of movement, including bradykinesia and apraxia. These motor symptoms, along the personality changes and cognitive decline, form the classic triad of symptoms of HD. Myoclonus, tics and tremor can also occur as part of the clinical spectrum of HD as well as choreoathetotic movements in the oro-bucco-facial regions that

progressively interfere with the voluntary control of vocalization, chewing and swallowing. General intellectual abilities show a mild diffuse impairment within the first year of onset of overt motor signs, but as the disease progresses, a more severe exacerbation of the early impairments produces a general intellectual state that will approach the range of mental retardation. The diagnosis of HD is established on the basis of genetic testing and to date there is no treatment available to modify the natural course of the disease.

5.2. Rodent Animal models Mouse models of HD can be classified into three different categories: (1) transgenic mice expressing exon-1 fragments of the human HTT gene containing polyQ mutations in addition to both alleles of murine wild-type huntingtin (Hdh); (2) knock-in mice with pathogenic CAG repeats inserted within the existing murine Hdh gene; and (3) mice that express the full-length human HTT gene in addition to the murine Hdh. The first reported transgenic mouse of HD was the R6 mice that overexpresses exon 1 of the mutated human HTT gene under the control of the human corresponding promoter (Mangiarini et al. 1996). This inserted gene harbored up 120 to 150 CAG-repeats and transgene is expressed at 31% of endogenous levels. These mice show a slow progression of the disease and limited nuclear inclusions. Many lines of R6 mice were generated afterwards; they differed mostly by the length of the repeats and by the level of expression of the transgene. To date, the most used mice are probably the R6/2 mice that contain 150 CAG repeats and that express the transgene at 75% of endogenous levels while the R6/1 line that has lower number of repeats and expression rate, show a more progressive course of disease. The R6/2 mice show weight loss and progressive and homogeneous motor deficits that start as early as 5-6 weeks and that become overt by 8 weeks (Carter et al. 1999). These behavioural phenotypes include tremor, clasping, convulsions that can be quantified on rotarod tests, grip strength and general locomotor activity assessment. Life expectancy of these mice is rather short (death occurs at 10-15 weeks of age), probably due to the extensive length of the CAG repeats which lead researchers to draw a parallel with the juvenile form of HD. Survival rates of R6/2 mice were used by researchers in neuroprotective studies and were shown to correlate well with improved motor behaviour (Dedeoglu et al. 2003; Jin et al. 2005). Histologically, these mice show cortical cerebellar and striatal atrophy, but with very little if any cell loss (Turmaine et al. 2000). Protein aggregates and inclusions containing

ubiquitine and HTT proteins were also observed but with an extent and distribution beyond what is found in HD (Davies et al. 1997). In addition, the HTT protein was found within the nucleus of cortical and subcortical neurons as also found in post mortem studies of HD patients’ brain and other CAG-repeat diseases (DiFiglia et al. 1997; Gutekunst et al. 1999). Interestingly, as shown by the team of A. Hannan, these mice when raised in an enriched environment show marked behavioural recovery and reduced volume loss implicating environmental conditions in this archetypical genetic disorder (reviewed in (Laviola et al. 2008)). Another line of mice in this category is the N171-82Q mice that harbor a longer Nterminal fragment of HTT than R6/2 mice with 82 polyQ (Schilling et al. 1999). These mice show striatal atrophy and a greater degree of cell loss but with more heterogeneity in the phenotype than R6/2 mice. Interestingly, rat model of transgenic HD with a truncated HTT fragment with 51 repeats under the control of the native HTT promoter exhibit adult-onset neurological phenotypes with progressive motor dysfunction and typical pathological alterations in the form of nuclear inclusions in the brain and shrinkage in striatal volume as well as reduced glucose consumption (von Horsten et al. 2003). The distribution of nuclear inclusions is rather limited as they were observed mainly in the striatum and globus pallidus; neuronal loss is moderate. These rats show progressive weight loss and die prematurely. The second category of mice with insertions of repeats within the mouse HTT gene showed discrete behavioural phenotype that was evident only when measures were performed during the night cycle, i.e., when mice are known to be generally more active (Menalled and Chesselet 2002). The mice with 111 CAG repeats inserted into the murine HD gene have a progressively developing nuclear phenotype that is specific for striatal neurons (Wheeler et al. 2000). These ubiquinated nuclear inclusions are seldom found in 10-18 month old mice. Some reactive gliosis was reported but with no cell loss or reduction in the brain volume whatever the region. Several lines of mice belonging to the third category, i.e, that harbor the full length IT15 gene, have been generated. The HD48Q and HD89Q transgenic mice have an insertion of the fulllength human IT15 gene under the control of the cytomegalovirus promoter (CMV). They show a progressive behavioural phenotype and striatal but also Purkinje neuronal loss, with a small degree of nuclear inclusions (Reddy et al. 1998). Alternative cloning vectors have been developed, they can be used for genomic fragments of up to 2 megabases for the yeast artificial chromosomes (YAC) (Slow et al. 2003) and up to

100 kilobases for bacterial artificial chromosomes (BAC) (Giraldo and Montoliu 2001). The YAC transgenic mice expressing the human IT15 gene with 48-128 repeats show a slow disease progression with motor abnormalities that range from initial hyperactivity, to impaired motor coordination and finally to hypokinesia. These behavioural changes are accompanied by almost exclusive striatal cell loss as well as nuclear and neuropil aggregates but in a lesser extension than the R6/2 mice. The BAC mice with 226 CAG repeats show tremor, head bobbing, curling at 3 months of age followed by hypoactivity at 6 months of age than death. Selective striatal and cerebral cortex neuronal loss was documented.

5.3. Invertebrate animal models Drosophila and Caenorhabditis elegans animal models were also used by researchers for screening purposes of genes and pathways that might be involved in neurodegenerative diseases or that might help manage the disorder. The use of these simple models, that present nevertheless several features of neuronal functions in higher organisms, have spurred recently as they offer a unique opportunity to dissect detailed mechanisms related to the development of neurodegenerative disorders. The first reports of polyQ repeats reported insertions of fragments of the human HTT gene that resulted in perinuclear cytoplasmic protein aggregation with repeats up to 150 folds but not with a lower number of repeats (2-95) (Faber et al. 1999; Satyal et al. 2000). This model has been used to identify evolutionary conserved suppressors

of

polyQ

toxicity

such

as

PQE-1

which

invalidation

exacerbated

neurodegeneration and cell death and which over-expression was protective (Faber et al. 1999). PolyQ insertions in Drosophila animal models yielded cell death and aggregate formation. Suppressor screens studies identified protein folding and clearance, RNA maturation and gene expression as essential steps in HD (Kazemi-Esfarjani and Benzer 2000). Indeed, two suppressors were identified that contain a chaperone-related J domain. One suppressor gene, dHDJ1, is homologous to human heat shock protein 40/HDJ1 while the second, dTPR2, is homologous to the human tetratricopeptide repeat protein 2. However, caution need to be exercised when interpreting results obtained in these simple animal models as they do not express the mutant gene in the same cellular phenotype as in human and intracellular pathways can sometimes be very different from higher model organisms.

5.4. Primate animal models 5.4.1 Lesioning approaches Earlier studies of HD most often used direct intrastriatal injection of kainaite or QA, a nonNMDA and NMDA glutamate agonists, to mimic the axon-sparing striatal lesion observed in HD (Ferrante et al. 1993; McGeer and McGeer 1976). However, as excitotoxic striatal lesions do not elicit persistent spontaneous motor symptoms this has led to the generation of toxininduced models to study mitochondrial impairment and excitotoxicity-induced cell death, which are both mechanisms of degeneration seen in the HD brain. These models, most of them based on 3-NP lesioning, are often used in HD studies (Brouillet et al. 1999). Interestingly, whereas the neurodegenerative effects were preferentially localized within the striatum, the decrease in SDH activity for a given dose of 3-NP was shown to be homogeneously distributed throughout the brain (Brouillet et al. 1998). The toxic effects of 3NP in the human were first discovered when farmers from China ingested sugarcane contaminated with the fungus Arthrinium. The metabolism of this fungus produces 3-NP which invariably caused cell death in the caudate and putamen with consequent appearance of persistent and severe dystonia in these intoxicated individuals (Ludolph et al. 1991). Systemic injection of 3-NP in non-human primates showed that a partial but prolonged energy impairment induced by the toxin is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration with preferential degeneration of the medium-sized spiny GABAergic neurons and a relative sparing of interneurons and afferents, as was observed in HD striatum (Brouillet et al. 1999).

5.4.2 Genetic approaches Genetic approaches using either local transfer of mutated HTT into the monkey striatum (Palfi et al. 2007) or, more interestingly, gene introduction into oocytes (Yang et al. 2008) seem to be the way forward in establishing HD models which closely replicate the pathogenesis of the human disease. By inserting a virus vector carrying part of the mutated human HTT gene, with 84 CAG repeats, into unfertilized monkey egg cells, a transgenic model of HD in a rhesus macaque that expresses polyQ-expanded HTT was developed. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were

observed in the brains of this model. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea (Yang et al. 2008). Because the nonhuman primates show neuroanatomical and behavioural characteristics that closely resemble those of humans, transgenic model in monkeys may show up to be the gold-standard animal model of neurodegenerative diseases and pave the way to generating non-human primate models for other neurological conditions that are caused by single-gene mutations, such as familial forms of PD, AD and ALS.

CONCLUSION The tremendous number of research focused on animal models of neurodegenerative diseases, and the impressive amount of data generated, clearly illustrate the significance of their use as a valuable research tool. However, research performed so far have also highlighted discrepancies between models and human neuropathology leading to question the pertinence of some of these findings to human disorders. As detailed above, a given pathology can be mirrored by numerous different animal models and determining which data obtained from these models are relevant to human pathology is problematic. Indeed, a mouse model simply carrying a human mutation or lesion is far from replicating the constellation of clinical symptoms, the pathogenic cascades and the neuroanatomic and neuropathologic changes observed in human pathology. This is especially true when the human pathology has no spontaneous equivalent in animals, which the case for most neurodegenerative disorders. In addition, the nature of the alteration performed in these models to mimic a neurodegenerative disorder, as well as features inherent to the animal models and their housing conditions, constitute also a drawback. For instance, animal models are often young males that are of an inbred species, thus almost genetically identical, and living in a very standardized environment. This is hardly the case of patients suffering from a neurodegenerative disorder. Given the tremendous amount of data currently available pointing to the implication of gender and gene/environment interactions in modulating brain function, one must use caution before translating findings in these animal models to human disorders (Laviola et al. 2008). Furthermore, the question addressed and the methodology used in the exploration of animal models are among the main factors of variance between clinical research, mostly performed on human subjects and post mortem brains, and more fundamental research on mouse models.

A clear and consensus definition of the criteria needed for a given animal model to be considered adequate is hard to reach among scientist and clinicians even for “straightforward pathologies” such as PD implicating mainly, but not only, degeneration of the nigral DA neurons or for HD due to a well defined genetic mutation. This is due to the wide spectrum of parameters defining a disease such as its onset, the related behavioural consequences and the underlying neuropathological features, rendering difficult the quest of generating the ultimate animal model. The challenge of obtaining such an ideal animal model is even greater in psychiatric disorders where the closest model to a human pathology is the drug addiction one, as attempts to model complex illnesses such as schizophrenia or depression remain, at best, unsatisfactory. Animal models are nevertheless still generated, sometimes following exquisite and complex constructions, mainly because of the complexities of the human brain and of disease processes and the inherent technical limitations of exploring the human disease by other means than on post-mortem brains. Although medical imagery procedures have gained significant and impressive advances this last decade, they do not provide elements to determine the pathogenesis of a disease or the causal chains involved. Thus, and despite their current limitations, animal models of neurodegenerative diseases are still essential elements in the laborious attempts to determine the etiology of a given disease, understand its progression and the relationship between the observed clinical phenotypes and the histological features or hallmarks of the disease. A growing need is now acknowledged to combine-join-converge research programs between clinicians and basic researchers who should reach for a consensual language. This should help extrapolate findings obtained in animal models to the human pathology and identify and apply means that will prevent or delay, if not cure, the disease.

Figure 1 legend : Schematic representation of six human brain tau isoforms. White boxes: three or four tubulin binding domains Grey boxes: inserts from exon 2 near the N-terminus Vertical lines in boxes: inserts from exon 3 near the N-terminus Black boxes : inserts from exon 10 near the N-terminus

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Subject Index ALZHEIMER’S DISEASE Age-related dementia Senile plaques Neurofibrillary tangles Amyloid precursor protein Presenilin A peptides Secretase Working memory Hippocampus Drosophila Melanogaster Caenorhabditis elegans Chimpanzee Nucleus basalis of Meynert Physostigmine and tacrine PARKINSON’S DISEASE Monogenic mutations Dopamine neurons Lewy bodies and Lewy neuritis
-synuclein Mitochondrial respiratory Tyrosine hydroxylase Apomorphine Amphetamine Rotations Stair-case test Cytoplasmatic inclusions Monoamine oxidase B The rotarod and open field locomotion tests Knockout mice MULTIPLE SYSTEM ATROPHY Levodopa unresponsive parkinsonism Cerebellar ataxia Oligodendroglial
-synuclein inclusion pathology Quinolinic acid 3-nitropropionic acid AMYOTROPHIC LATERAL SCLEROSIS Motor neuron disease Copper/zinc superoxide dismutase 1 gene Bunina bodies Skeins-like inclusions Round hyaline inclusions Hyaline inclusions Alsin HUNTINGTON DISEASE Expanded trinucleotide CAG repeat Huntingtin Chorea and dystonia

PolyQ mutations CAG repeats R6 mice The full length IT15 gene Cytomegalovirus promoter Yeast artificial chromosomes Bacterial artificial chromosomes Rhesus macaque

Fig 1.