Oxidative Stress and Alzheimer Disease

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Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, ... Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H,.
[Autophagy 2:2, 143-145, April/May/June 2006]; ©2006 Landes Bioscience

Oxidative Stress and Alzheimer Disease Addenda

The Autophagy Connection?

ABSTRACT Intraneuronal accumulation of amyloid β-protein (Aβ) is believed to be responsible for degeneration and apoptosis of neurons and consequent senile plaque formation in Alzheimer disease (AD), the main cause of senile dementia. Oxidative stress, an early determinant of AD, has been recently found to induce intralysosomal Aβ accumulation in cultured differentiated neuroblastoma cells through activation of macroautophagy. Because Aβ is known to destabilize lysosomal membranes, potentially resulting in apoptotic cell death, this finding suggests the involvement of oxidative stress-induced macroautophagy in the pathogenesis of AD.

KEY WORDS Alzheimer disease, amyloid β-protein, autophagy, lysosomes, oxidative stress

Addendum to: Autophagy of Amyloid β-Protein in Differentiated Neuroblastoma Cells Exposed to Oxidative Stress

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L. Zheng, K. Roberg, F. Jerhammar, J. Marcusson and A. Terman Neurosci Lett 2006; In press.

Alzheimer disease (AD), the leading cause of senile dementia, is manifested by progressive brain atrophy and histological hallmarks such as intraneuronal neurofibrillary tangles, rich in hyperphosphorylated protein tau and extraneuronal senile plaques, mainly composed of β-amyloid fibrils.1,2 Fibrillar β-amyloid is assembled from monomeric amyloid β-protein (Aβ), which in turn forms due to intracellular β-amyloid precursor protein (APP) processing.1,2 The pathogenesis of AD is far from being clear. Accumulating evidence indicates the importance of intraneuronal Aβ accumulation, which is believed to promote death of neurons or degeneration of neuronal processes, resulting in senile plaque formation.2,3 Along with intracellular increase of Aβ, oxidative damage to neurons4,5 and activation of macroautophagy6 (hereafter referred to as autophagy) have been reported to occur early in AD, implying that these early neuronal changes might be interrelated. Our recent observation7 provides a possible link between oxidative stress and autophagy in AD pathogenesis. Using double immunostaining for Aβ and lysosomal-associated membrane protein 2, we have found that retinoic acid-differentiated SH-SY5Y neuroblastoma cells exposed to mild oxidative stress (i.e., 40% versus 8% ambient oxygen) for five days accumulated large, over 1 µm in diameter, Aβ-containing lysosomes, which were not typical of control cells. Intralysosomal accumulation of Aβ (demonstrated for both Aβ1-42 and Aβ1-40) was suppressed by the sequestration inhibitor 3-methyladenine, suggesting that Aβ entered lysosomes through autophagy (Aβ-containing lysosomes thus represent autophagolysosomes). Aβ endocytosis was excluded by a separate localization of Aβ and the early endosomal marker rab5, while electron microscopy showed increased numbers of autophagosomes and autophagolysosomes in oxidative stress-exposed cells (classification of autophagy-related structures is reviewed in refs. 8 and 9). Our in vitro observation is consistent with a recent finding of Aβ within neuronal lysosomes of transgenic mice expressing mutant human APP and presenilin-1.10 It is reasonable that neuroblastoma cells responded to oxidative damage by activation of reparative autophagy, resulting in the intralysosomal accumulation of cytoplasmic Aβ. Also, as suggested by earlier findings,11,12 oxidative stress could enhance amyloidogenic APP processing thereby increasing the total intracellular Aβ as well as the quantity of autophagocytosed Aβ. In view of a recent report by Yu et al.,13 implicating autophagic vacuoles as a site of amyloidogenic APP processing, oxidant-induced intralysosomal accumulation of Aβ could occur through the enhancement of APP autophagy and resulting increased Aβ formation within autophagic vacuoles. It remains to be elucidated whether intralysosomal Aβ represents autophagocytosed cytoplasmic Aβ, or a derivative of autophagocytosed APP, or both. Diminished degradation of Aβ by lysosomal enzymes14 can be an additional reason for its intralysosomal accumulation following oxidative stress. Theoretically, oxidative stress can either decrease the activity of lysosomal enzymes, or modify the structure of Aβ making it less prone to hydrolysis, as is the case for proteins that give rise to lipofuscin, an intralysosomal undegradable material.15 Possible mechanisms of oxidant-induced increase of lysosomal Aβ are summarized in Figure 1.

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Previously published online as a Autophagy E-publication: http://www.landesbioscience.com/journals/autophagy/abstract.php?id=2444

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Received 12/28/05; Accepted 12/28/05

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*Correspondence to: Lin Zheng; Division of Geriatric Medicine; Faculty of Health Sciences; Linköping University; SE-58185 Linköping, Sweden; Tel.: +46.13.222271; Fax: +46.13.221529; Email: [email protected]

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Division of Geriatric Medicine; Faculty of Health Sciences; Linköping University; Linköping, Sweden

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Lin Zheng* Jan Marcusson Alexei Terman

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Oxidative Stress, Autophagy and Alzheimer Disease

Figure 1. Possible mechanisms of oxidant-induced Aβ accumulation within lysosomal compartment. Aβ forms due to APP processing and is transported within specific cytoplasmic vesicles (not shown). Important sites of amyloidogenic APP processing are endosomes and autophagolysosomes, which are responsible for the cleavage of APP delivered from the plasma membrane and intracellular locations (e.g., endoplasmic reticulum and Golgi complex), respectively. Oxidative stress, usually associated with increased mitochondrial production of hydrogen peroxide, induces reparative autophagy that delivers additional amounts of Aβ to autophagolysosomes. Oxidative stress might also increase autophagolysosomal content of Aβ by enhancing APP processing (in particular, as a result of increased autophagy of APP) or by inhibiting degradation of Aβ by lysosomal enzymes. APLS, autophagolysosomes; APS, autophagosome; EE, early endosome; GDV, Golgi-derived vesicles; LE, late endosome; LYS, lysosome; Mt, mitochondria; TGN, trans-Golgi network. References are given in the text.

Whatever the precise mechanism of oxidant-induced intralysosomal Aβ accumulation, it can potentially result in lysosomal membrane rupture, culminating in neuronal apoptosis, as follows from the toxicity of exogenous Aβ1-42 (being less soluble, more resistant to degradation and more toxic than Aβ1-40) to cultured cells.16,17 An important factor of Aβ1-42 toxicity is its pro-oxidant activity in the presence of transition metals such as iron and copper.5,18 An increased iron and copper content of lysosomes, as compared to other cellular compartments,19 would lead to greater oxidative stress in the presence of Aβ1-42, favoring increased autophagy and further accumulation of Aβ. Oligomerization of Aβ has been recently recognized as an important factor of its toxicity. Aβ oligomers accumulate within AD neurons3 and can induce neuronal dysfunction20,21 and apoptotic cell death.22 It would be of interest to learn whether oxidant-induced intralysosomal accumulation of Aβ also involves its oligomerization. Normal oxygen metabolism is known to be associated with continuous electron leak, resulting in minor oxidative damage to cellular components, the accumulation of which is believed to result in aging23 and age-related pathologies including AD.24 Oxidantinduced damage mainly accumulates within long-lived postmitotic cells such as neurons and cardiac myocytes that neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. In view of our findings, this continuous “normal” oxidative stress would result in gradual accumulation of Aβ within neuronal lysosomes that finally may reach the level resulting in cell death. Obviously, this process will be accelerated in individuals with familial AD. It should be pointed out that our understanding of the mechanisms behind intraneuronal Aβ accumulation in AD would benefit from the knowledge of Aβ metabolism and transport in normal cells. Although immunoelectron microscopy of normal brains reveals association of Aβ with multivesicular bodies,25 the latter remain basically uncharacterized by organelle-specific molecular markers. In differentiated neuroblastoma cells, the majority of Aβ-positive granules were not colocalized with markers specific for lysosomes, endosomes or secretory vesicles (Zheng et al., unpublished results). Both endocytic26 and autophagic13 pathways are currently considered to be involved in Aβ formation from APP. Although cellular sites of APP processing need to be further clarified, both pathways can potentially deliver Aβ to lysosomes. 144

Thus, there is emerging evidence implicating the role of the autophagic-lysosomal system in Aβ production, its abnormal accumulation within AD neurons, and resulting apoptotic cell death. Better understanding of this role would help developing new strategies for prevention and therapy of AD. References 1. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004; 430:631-9. 2. Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Aβ accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging 2005; 26:1235-44. 3. Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK. Oligomerization of Alzheimer’s β-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 2004; 24:3592-9. 4. Pratico D. Alzheimer’s disease and oxygen radicals: New insights. Biochem Pharmacol 2002; 63:563-7. 5. Zhu X, Raina AK, Lee HG, Casadesus G, Smith MA, Perry G. Oxidative stress signalling in Alzheimer’s disease. Brain Res 2004; 1000:32-9. 6. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64:113-22. 7. Zheng L, Roberg K, Jerhammar F, Marcusson J, Terman A. Autophagy of amyloid β-protein in differentiated neuroblastoma cells exposed to oxidative stress. Neurosci Lett 2006; In press. 8. Levine B, Klionsky DJ. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6:463-77. 9. Terman A, Brunk UT. Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005; 68:355-65. 10. Langui D, Girardot N, El Hachimi KH, Allinquant B, Blanchard V, Pradier L, Duyckaerts C. Subcellular topography of neuronal Aβ peptide in APPxPS1 transgenic mice. Am J Pathol 2004; 165:1465-77. 11. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid β-protein (Aβ) in human neuroblastoma cells. Biochemistry 2000; 39:6951-9. 12. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 2005; 92:628-36. 13. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy-a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 2005; 171:87-98. 14. Nakanishi H. Neuronal and microglial cathepsins in aging and age-related diseases. Ageing Res Rev 2003; 2:367-81. 15. Terman A, Brunk UT. Lipofuscin. Int J Biochem Cell Biol 2004; 36:1400-4. 16. Yang AJ, Chandswangbhuvana D, Margol L, Glabe CG. Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Aβ1-42 pathogenesis. J Neurosci Res 1998; 52:691-8. 17. Ditaranto K, Tekirian TL, Yang AJ. Lysosomal membrane damage in soluble Aβ-mediated cell death in Alzheimer’s disease. Neurobiol Dis 2001; 8:19-31. 18. Butterfield DA, Bush AI. Alzheimer’s amyloid β-peptide (1-42): Involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Neurobiol Aging 2004; 25:563-8.

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