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Using electron microscopy, thioflavin T assay and Congo red binding showed that NAP inhibited the formation of the mesh network of aggregated Aβ peptides.

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Current Drug Metabolism, 2015, 16, 346-353

Therapeutic Interventions for the Suppression of Alzheimer’s Disease: Quest for a Remedy Naveed Ahmad Fazili1, Aabgeena Naeem1,*, Ghulam Md. Ashraf 2, Siew Hua Gan3 and Mohammad A. Kamal2,4 1

Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, U.P., India; 2King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; 3Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia; 4Enzymoic, 7 Peterlee Pl, Hebersham, NSW 2770, Australia

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Abstract: Protein aggregation is facilitated by the generation of partially folded intermediates that lack most of the tertiary interactions, but retain the complete secondary structure. These partially folded states cross-link each other to form protein aggregates. Protein aggregates in an advanced stage result in the formation of amyloid fibrils, which have high tensile strength. These amyloid fibrils are associated with a number of pathologies, especially Alzheimer’s disease, which involves the aggregation of the A peptide. In recent years, much attention has been paid to the generation of potent therapeutics to reduce A peptide fibrillation. This review summarizes the range of molecules used for this therapy, showing their potency against A amyloids, and suggests a positive future for the eradication of this dreaded disease.

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This review primarily sheds light on the process of protein aggregation and amyloid formation, which is the mechanism involved in the formation of A aggregates. Afterwards, the relevance of the A aggregates to AD is discussed. Moreover, we summarize the knowledge gained from studies related to AD eradication, including the investigation of agents that target A aggregates. Finally, we hypothesize that the full eradication of AD is near, due to the range of molecules and agents that can potentially be used to treat this disorder. 2. PROCESS OF PROTEIN AGGREGATION

Protein aggregation is a phenomenon whereby a protein loses its native structure and adopts a non-native conformation, leading to *Address correspondence to this author at the Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202 002, India; Tel: +919997607218; Fax: +91 0571 2706002 E-mails: [email protected]; [email protected] 

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Alzheimer’s disease (AD) was named after the German neuropathologist Alois Alzheimer, who was the first to report the relationship between cognitive impairment and the presence of amyloid plaques in the brain of the affected individuals [1]. AD is the most common form of age-related neurodegeneration and affects in excess of 12 million people worldwide [2]. It is mainly the outcome of the aggregation of the A peptide, which is driven by certain mutations in the amyloid precursor protein gene located on chromosome 21; these mutations primarily alter the native state of the protein, leading to its aggregation [3-7]. For example, CRND8 transgenic mice, which carry a mutant gene for the Alzheimer precursor protein (APP), exhibit AD-like phenotypes as a result of the aggregation of the A peptide [8]. This A peptide forms insoluble fibrils that later appear in the form of either senile plaques or neurofibrillary tangles [9] in the cerebral cortex of the brain, representing the pathological hallmark of AD [10]. AD is characterized by a progressive loss of memory, task performance, speech and recognition of people and objects as a result of severe neurodegeneration [11].

aggregation [12]. In other words, we can say that a partially folded state forms the molecular basis for the formation of protein aggregates. In fact, the partially folded states form cross-linked structures as a result of the intermolecular interactions between different molecules, termed ‘non-specific co-aggregation,’ or between the same molecule, termed ‘specific aggregation’. In these partially folded states, the protein becomes somewhat loosely packed and its hydrophobic residues become exposed to the solvent, thus enhancing the chances that oligomeric assemblies will form. In this state (aggregated state), the -sheet content generally increases [13-16]. These -sheets serve as a template to which other misfolded molecules are recruited, thus increasing the size of the protein aggregates [17]. Stretches of polypeptide chains with a high -sheet content appear to play a more important role in the aggregatio n process than those with -helical secondary structure. The intrinsic instability of the unfolded state, due to the low transition energy, and/or the relative stable folding intermediate that escape the protein quality control mechanism are prerequisites for aggregate formation [18].

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1. INTRODUCTION

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Keywords: A peptide, Alzheimer’s disease, amyloid fibrils, protein aggregates, nanotechnological approach.

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The aggregation process involves three phases. Initially, there is the generation of off-pathway intermediates, which are termed ‘aggregation prone precursors’ [19]. The ease with which a partially folded state is generated determines the rate at which the aggregates are formed. The proteins that are intrinsically disordered, such as synuclein, are highly susceptible to aggregate formation, as a partially folded state is easily accessible because these proteins do not possess a compact tertiary structure. Moreover, the helical regions of proteins, which have the tendency to form extended -sheet conformations, are also prone to aggregation [20-22]. Apart from the conformational status of the proteins, the lifetime of the partially folded state also helps to determine the formation of aggregates. Those proteins with a longer lifetime are more susceptible to the formation of protein aggregates [23]. The second phase is termed as the ‘nucleation phase’, in which the intermediates assemble together into oligomers in a specific orientation to form a structure that is described as the ‘nuclei’ [24]. In the third phase, the ‘po© 2015 Bentham Science Publishers



Current Drug Metabolism, 2015, Vol. 16, No. 5

Therapeutic Interventions for the Suppression of Alzheimer’s Disease

Proteins aggregates have been classified into two main types based on their morphology: particulate type and spherulite structure [25]. The particulate type of protein aggregates has a uniform size and is specifically found in the milk protein -lactoglobulin. This type of aggregate structure is normally developed around the protein’s isoelectric point and can be visualized using confocal microscopy. Particulate aggregates have been proposed to serve as a vehicle in drug delivery systems due to their uniform size [26]. The spherulite type of protein aggregates eventually form fibrils that radially grow from a central core and can be seen with the aid of polarized light microscopy. The spherulite type of fibrils has been identified in the aggregation process of two vital proteins, insulin and -lactoglobulin [27].

4. A FIBRIL: A SPECIFIC CASE OF AMYLOID FORMATION -amyloid could be considered as a special case of fibril formation due to its association with the development of AD [34]. The A peptide is normally produced as a soluble and non-toxic peptide of either 40 or 42 residues; this peptide is derived from the processing of the transmembrane glycoprotein amyloid precursor protein (APP) through the action of the  and  secretases [35]. However, mutations in the gene encoding APP, the immediate precursor of the A peptides, or the genes involved in APP processing, such as the genes encoding the  and  secretases, can facilitate the conversion of the soluble and non-toxic form of A peptides into A amyloids, which are neurotoxic [36-41]. One of the mutations that facilitates the onset of AD and the formation of A amyloids is the D678N mutation in the APP gene; this mutation occurs in exon 16 and causing a nucleotide transition that changes GAC to AAC. This mutation results in the substitution of an aspartate with an asparagine residue at position 7 of the A peptide [42]. Another mutation that facilitates the occurrence of A aggregates is the D7N mutation. This mutation results in the nucleotide transversion from GAC to CAC, causing the substitution of aspartate with histidine at position 7 of the A peptide. This amino acid substitution causes the equilibrium to shift towards a greater A1-42 / A1-40 ratio. Moreover, the D7N amino acid substitution (aspartate to histidine) facilitates the binding of Zn2+ and Cu2+, which actually accelerate the formation of A amyloids [43]. It has also been reported that the APP I71mutation, which results in the substitution of an isoleucine with a valine, causes A aggregation involving the A1-42 peptide [44]. Another mutation in APP (E693G), which has been termed as

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Protein aggregates form higher order structures by developing a fibrillar structure, which is termed an ‘amyloid’ [25]. Amyloids differ from inclusion bodies in a sense that the former is deposited extracellularly, while as the latter appears in the intracellular region [28]. Most of the amyloids associated with pathological states are unbranched and straight, with a diameter of nearly 40-120 Å [29]. Amyloid fibrils are, in turn, composed of 2 to 5 smaller protofilaments. These protofilaments are rich in -sheet content, with strands running perpendicular to the fibril axis [30, 31]. Amyloid fibrils usually have a similar external morphology, despite the fact that the proteins involved in fibril formation have varied sequences, thus suggesting that fibril formation involves a similar core mechanism [32]. Amyloid fibrils have a high tensile strength equivalent to

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3. FROM AGGREGATES TO AMYLOIDS

that of steel and a mechanical stiffness equivalent to that of silk (1-10 Gpa) [33]. The transformation from the native state of protein to the amyloid structure has been shown in (Fig. 2).

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lymerization phase’, the oligomeric structures formed in the nucleation phase assemble together to form amyloid fibrils in a mesh-like network with high tensile strength [23]. The three phases of this folding pathway have also been depicted diagrammatically (Fig. 1).

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Fig. (1). Sequence of events depicting the ‘amyloid cascade hypothesis’. Mutations to the amyloid precursor protein (APP) gene generate A amyloids, which result in neuronal cell death and facilitate the occurrence of Alzheimer’s disease (AD).

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5. AGENTS AIMED AT BLOCKING A AGGREGATION: POSSIBLE REMEDIES FOR AD

to be a potent therapeutic agent that inhibits A peptide fibrillation. Electron microscopic images showed that 50 μM silibinin inhibited A aggregate formation; in this experiment, the control image showed extensive fibril formation, while the silibinin-treated sample showed almost no fibrillar pattern, indicating that silibinin treatment resulted in the disaggregation of the fibrils. Moreover, the ThT assay confirmed that an increase in silibinin concentration from 0 to 100 μM resulted in an increase in the percent inhibition of fibril formation from 0 to 70 %. Moreover, the attenuation of neuronal damage was also examined using the human SH-SY5Y cell line, and it was found that cell viability also improved in a dosedependent manner. Additionally, H2O2, which was originally produced by the presence of the A aggregates, was present in smaller levels after silibinin treatment. Thus, there is reason to believe that silibinin could emerge as a strong anti-aggregating agent, which would raise the possibility of AD eradication [53].

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the arctic mutation, causes an increase in A fibril formation in vitro and intraneuronal A aggregates in vivo [45]. This transformation involves a chain of events and eventually leads to the production and subsequent aggregation of A peptides, a process that is known as the ‘amyloid cascade hypothesis’ [46, 47]. The A peptide with 42 residues is more susceptible to aggregate formation than the A peptide with 40 residues. A1-42 and A1-40 are two different isoforms that are produced during the conversion of the amyloid precursor protein into functional A peptides [48].

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Fig. (2). The transformation from the native state of a protein into a mature amyloid fibrillar structure involves three phases. In Phase 1, aggregation prone intermediates are produced. In phase 2, or the ‘nucleation phase’, toxic oligomers are formed. In phase 3, or the ‘polymerization phase’, the toxic oligomers polymerize to form amyloid fibrils.

5.1. Curcumin

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Curcumin (curcuma longa) has shown positive results against the fibrillation of the A peptide [49]. The major advantage of curcumin as an anti-aggregating agent against A amyloids is that it easily crosses the blood-brain barrier due to its hydrophobic nature. Experiments performed in Tg2576 transgenic mice, which possess a mutant APP gene, showed that curcumin bound to the amyloid plaques, as revealed by the brain sections of the mice. There was a yellow green fluorescence that was visualized with the aid of a fluorescence microscope. Studies have shown that curcumin dosedependently inhibited the aggregation of A fibrils using ELISA, dot blot and electron microscopy analyses. The features of curcumin that contribute to its anti-aggregation property include the hydroxyl substitution on the aromatic end group, a narrow linker length ranging from 8 to 16 Å and the presence of a second terminal phenyl group [50]. Another possible mechanism behind the inhibition of A amyloid aggregation by curcumin is that curcumin activates brain macrophages, which in turn facilitate the clearance or phagocytosis of the A aggregates from the interior of neuronal cells. Thus, curcumin could be a possible therapeutic for the treatment of AD [51].

5.3. Rifampicin Rifampicin is an important bactericidal antibiotic. In a study conducted by a group of workers, it was found that the rifampicin is quite potent against aggregates of the A1-40 peptide involved in the pathogenesis of AD. Using electron microscopy analysis, it was found that the amyloid fibrils of the A peptide, which were present in the control sample, disappeared when the A peptide aggregates were treated with rifampicin. Moreover, the ThT assay, which uses an amyloid specific dye, showed a decrease in fluorescence intensity compared to the sample containing only the A aggregates, which displayed high fluorescence intensity [54]. It is actually the naphtha hydroquinone or naphthoquinone structure that facilitates the clearance of the A aggregates. Moreover, the ansa chain, which has nothing to do with the inhibition mechanism, facilitates the transport of antibiotic across the blood-brain barrier due to its lipophilic nature, allowing it to interact with the A aggregates [55].

5.2. Silibinin

5.4. Beta Sheet Blockers (BSB)

Silibinin is a flavonoid that was isolated from milk thistle (Silybum marianum) [52]. Recent work has suggested that it could prove

One of the BSB is a short peptide termed NAP, which was derived from a natural neurotropic protein and can be delivered to

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interaction of estrogen, especially estrone (E1), estriol (E2) and estradiol (E3), with A1-42 and A1-40 peptides involve electron microscopy and thioflavin T analyses. From these two very important and authentic assays, it was demonstrated that all of the variations of estrogen (E1, E2 and E3) inhibited the fibrillation of both the A1-42 and A1-40 peptides in a dose-dependent manner. Therefore, targeting A1-42 or A1-40 fibrillation could reverse the complexity of AD [67]. The most possible mechanism behind the fibril destabilizing and anti-amyloidogenic effects of estrogen is that estrogen attaches to the ends of the extending A1-42 or A1-40 fibrils and enhances the rate of depolymerization by stabilizing the conformations of the A peptides that have just been incorporated into the fibril ends [68]. To add to the authenticity of estrogen as an antifibrillation agent, researchers found that APP23 transgenic mice, which have reduced levels of estrogen, exhibited accelerated A plaque formation [69]. 5.8. -Tocopherol

RRR--tocopherol quinone (-TQ), which is the main derivative of -tocopherol, has been shown to have positive results against A peptide fibrillation [70]. This compound has been suggested as an ‘A targeting’ therapy, as it suppresses the aggregation of the toxic protein (A) and serves as a free radical scavenger [71, 72]. CD fluorescence measurements, electron microscopy and thioflavin T assay demonstrated that -tocopherol quinone could serve as a possible therapy against AD. The thioflavin T assay clearly emphasized that -TQ inhibited the fibrillation of the A peptide. A1-42 alone displayed a high fluorescence intensity; however, there was a sharp dose-dependent decrease in the fluorescence intensity when the samples were incubated with 30 or 300 μM TQ. Moreover, the CD measurements showed that the band at 215 nm, which corresponds to -sheet structure, disappeared in the presence of the above mentioned concentrations of -TQ. Thus, the CD measurements support the findings of the thioflavin T assay, as -sheet content increases during aggregate formation. Finally, TEM (transmission electron microscopy) images showed that the fibrils present in the control (A peptide aggregated in vitro) were strongly disrupted upon the addition of 30 or 300 μM -TQ, as the images corresponding to the treated samples displayed no fibrillar network [70]. The most plausible mechanism behind the inhibitory effect of -TQ is that -TQ has one H-bond donor in its side chain and three H-bond acceptors in the -TQ central ring; thus, this compound interacts with the A peptide via H-bonds. Both faces of the electron-poor (+) central ring of -TQ can interact with the two electron-rich (_) carbonyl oxygens in the amino acid chain of the A peptide, resulting in +_ interactions. These interactions facilitate the destabilization of the inter-strand H-bonds within the A aggregates and caused the A fibrils to disaggregate. Moreover, -TQ contains a long hydrophobic side chain that may interact with the hydrophobic region of A42 via hydrophobic interactions, thus blocking the fibrillation process [73].

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5.6. Theaflavins

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Galantamine is an acetylcholinesterase inhibitor (AChEI) drug [60]. It is an alkaloid mostly isolated from the Caucasian snowdrop Galanthus woronowii. Currently, it is considered a potent drug against AD. With the aid of electron microscopy, it has been shown that galantamine inhibits the formation of A fibrils. In fact, the negatively stained electron micrographs suggest that the A1-40 peptide forms a dense meshwork of fibrils when incubated under in vitro conditions, which served as a control. However, when these control samples were treated with 200 μM galantamine, the fibrillar pattern was greatly reduced, reflecting the anti-inhibitory activity of galantamine [61]. One possible reason for this inhibition was demonstrated by NMR studies; these studies implied that the aromatic ring of galantamine binds to phenylalanine residues that are important in the aggregation process, as the peptide sequences containing the KLVFF motif are central to the fibril formation process [62].

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5.5. Galantamine

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the central nervous system via intranasal administration [56]. NAP is composed of the amino acids asparagine, alanine, proline, valine, serine, isoleucine, proline and glutamine. This peptide has been shown to be a potent agent against the fibrillar pattern of the A amyloids. Using electron microscopy, thioflavin T assay and Congo red binding showed that NAP inhibited the formation of the mesh network of aggregated A peptides. This inhibition could be due to the fact that the NAP peptide has a long hydrophobic core of 6 amino acid residues, including two proline residues that serve as beta sheet blockers. Thus, NAP has a molecular structure that prevents the fibril formation of the A peptide by blocking -sheet formation [57]. Another BSB, the peptide (Ac-L1-V2 (NMet) F3-F4A5-NH2), has also been reported to block the aggregation pathway of the A peptide1-42. Stepwise docking studies were performed to find the exact interaction sites between the above mentioned BSB and the A peptide. From the docking calculations, it was concluded that the BSB (Ac-L1-V2 (NMet) F3-F4-A5-NH2) specifically bound to the site spanning residues 17-20 of the A peptide [58]. This 17-20 residue sequence is critical in the generation of the A aggregates. Binding of this BSB to the region spanning residues 1720 facilitates the inhibition of A aggregate formation, which could possibly be a step in the development of an AD remedy [59].

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Theaflavins are produced during the oxidation process of green tea containing EGCG (epigallocatechin gallate) [63]. These theaflavins are basically polyphenolic compounds that are formed by the quinonic condensation of the catechin structure [64]. Atomic force microscopy (AFM) and thioflavin T assay clearly demonstrated the anti-amyloidogenic propensity of the theaflavins, especially TF3. AFM images clearly showed that the amyloid fibrils disappeared in the presence of theaflavin when present in a 1:1 ratio. Moreover, the thioflavin T intensity greatly diminished compared to the control, suggesting the anti-inhibitory effect of theaflavins against A peptide aggregation [65]. The most plausible reason behind the inhibitory effect of theaflavin TF3 could be that the TF3 cyclic structure interacts with amino acids 16-22 of the A peptide; these residues constitute the hydrophobic region and binding of TF3 blocks the intermolecular interactions, thus preventing the aggregation of the individual molecules and the formation of amyloids [66]. 5.7. Estrogen Estrogen is a female sex hormone. It has also been shown to be a potent inhibitor of A peptide fibril formation and may be a potential remedy for the eradication of AD. Studies investigating the

5.9. Nicotine There are two optical enantiomers of nicotine termed D(+) and L(-) [74]. L(-) nicotine is the biologically active form of nicotine [75]. The ThT assay and EM analyses found that both enantiomers of nicotine were effective at inhibiting the fibrillation pattern of A (1-40). It was quite evident from the EM images that the fibrils were disrupted in the presence of 800 μM of D(+) or L(-) nicotine. Moreover, ThT fluorescence data suggested that there was a decrease in the fluorescence intensity of the A (1-40) peptide samples treated with D( +) or L(-) nicotine compared to the control sample. The most valid reason for the inhibitory action of nicotine

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reducing bulk materials [89]. Because nanoparticles involve the creation and/or manipulation of materials at the nanometer scale, they could be quite useful in addressing the neuropathological states [90]. In recent years, different types of nanoparticles, nanocapsules and nanoconstructs have been engineered, including polymeric nanoparticles [91], polymeric nanospheres and nanosuspensions [92], polymeric nanogels [93], carbon nanotubes and nanofibers [94], polymeric nanomicelles [95] and polymeric nanoliposomes [94]. These approaches have shown some promising results, but considerable further research is necessary.

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The amyloid cascade hypothesis has now dominated the field of AD for many years [96] and modern approaches to counter the amyloid cascade hypothesis have not succeeded [97]. As a new and promising approach, nanoparticles could play a vital role in overcoming the formation of A amyloids, which are the main culprits in the pathogenesis of AD. In this regard, numerous studies have been performed to discover anti-aggregating or neutralizing agents that prevent the fibrillation of the A1-42 peptide. This A1-42 peptide is the most neurotoxic of all the A peptide isoforms due to its greater tendency to form aggregates and amyloids [98]. In one study, it was found that a poly alkyl cyanoacrylate (PACA) nanoparticle strongly adsorbs A1-42 fibrils to its surface when treated with polyethylene glycol (PEG) [99]. This adsorption of A1-42 fibrils to the surface of PACA was tested in vitro (in solution) and in vivo (in serum) using confocal microscopy and surface plasmon resonance. The nanoparticle-fibril interaction did not activate the complement system, which is part of the innate immune defense. This feature is quite significant in terms of nanoparticle safety and its clearance kinetics from the blood. As a result of the adsorption, the PACA nanoparticle carries the A1-42 amyloid fibril all the way to the liver, where it is degraded and processed by hepatic macrophages, thus cleared from the system. Therefore, the nanoparticle serves as a peptide sequester and facilitates clearance via the ‘sink effect’ [99]. In another study, it was shown that indomethacin loaded lipid core nanoparticles (IndOH-LNCs) can delay the development of AD [100]. Initially, the A1-42 peptide was administered to rats at a concentration of 1 nmol/site via an intracerebroventricular route; administration of the A1-42 peptide can result in the formation of A amyloid plaques in vivo. Twenty-four hours after the A1-42 peptide injection, the rats were intraperitoneally injected with either free IndOH or IndOH-LNCs (1 mg/kg) for 14 days. Surprisingly, only the IndOH-LNC treatment markedly reduced the effects caused by the intracerebroventricular administration of A1-42 and overcame the inhibition of microglial activation and neuroinflammation. This work suggested that IndOH-LNC could prove to be a positive therapeutic agent for AD [100]. Another important study assessed the effect of gold nanoparticles (AuNPs) on the aggregation pattern of A amyloids and it was concluded that poly acrylic acid (PAA) coated gold nanoparticles, with a diameter of at least 18 nm, could block the aggregation of A peptides, thus suggesting that surface coated AuNPs could be explored as a therapeutic strategy for AD [101]. Some other recent findings also support the quest for neurodegenerative remedy [102106].

5.10. Ferulic Acid (FA)

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FA is a well-known phenolic compound that possesses antioxidant properties and has also been shown to reduce neurotoxicity [82-85]. In a study examining the effect of FA on the aggregation of the A peptide, it was found that FA destabilized and disaggregated the A fibrils in a concentration-dependent manner. The thioflavin T assay showed that fresh A1-40 and A1-42 peptides at concentrations of 50 and 25 μM, respectively, showed an increase in fluorescence intensity when incubated at 37°C; the fluorescence intensity exhibited a lag phase, which was not present when preformed A fibrils were added, followed by a nucleation-dependent polymerization model and this increase in fluorescence intensity was significantly decreased in the presence of 50 μM FA. The EM results further supported the results of the ThT assay and showed that 50 μM FA could destabilize A fibrils when incubated for 6 hours. Thus, FA has been shown to possess anti-amyloidogenic properties and could be a potential treatment for AD [85]. The most possible mechanism for the anti-aggregating potential of FA is that it interacts with the Asp23-Lys28 salt bridges by orienting its carboxyl groups towards the positively charged side chain of lysine. This interaction competes with aspartate binding and disrupts the AspLys arrangement. This, in turn, causes an increase in the solvation of this region and the unpacking of the chains, which facilitates fibril destabilization. Therefore, it could be suggested that the partial insertion of FA between the oligopeptides can interfere with the association of the incoming A peptides and thus inhibit their reassociation in the association-dissociation dynamic equilibrium. These effects form the basis for the inhibition of fibril elongation [86].

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on the aggregation pattern of the A (1-40) peptide is that the nicotine molecules can interact with the histidine residues at positions 6, 13 and 14, which results in an increased distance between the peptide monomers, thus delaying the onset of aggregation [76]. Moreover, nicotine influences the accumulation of the senile plaques formed by the aggregation of the A1-40 or A -42 peptides by stimulating nicotinic acetylcholine receptors that interfere with the processing of the -amyloid precursor protein, thus affecting the aggregation process of the A peptides [77-79]. Additionally, nicotine also has anti-oxidant properties and facilitates the scavenging of hydroxyl free radicals, which are produced during the incubation of the A peptide. It has been experimentally shown that hydroxyl free radicals facilitate the generation of aggregates. Therefore, overcoming the generation of hydroxyl free radicals through the anti-oxidant activity of nicotine could be an important reason why nicotine delays or completely blocks A aggregation [80]. In light of this study, it has been postulated that smoking can reduce the risk of developing AD; indeed, transgenic mice that were given chronic nicotine treatments showed reduced plaque density in the neocortex and the hippocampus regions of the brain [81].

6. NANOTECHNOLOGICAL APPROACH TO CURB AD Alzheimer's disease is a progressive neurological disease of the brain that leads to the irreversible loss of neurons and intellectual abilities, including memory and reasoning, which become severe enough to impede social or occupational functioning [87]. Because AD mainly affects brain function, an effective treatment approach should be capable of traversing the blood-brain barrier (BBB). In this regard, nanoparticles have become an object of interest as they are efficient drug delivery systems that can traverse the BBB, as opposed to most pharmaceuticals and other small molecules, which are unable to cross this formidable check point [88]. Nanoparticles are formed by scaling up single groups of atoms or by refining or

7. CONCLUDING REMARKS A wide range of compounds and aggregation strategies have been developed to curb the menace of AD. For that purpose, the mechanism of A aggregate formation has been described in great detail and the progression of the A peptide from the soluble state to the aggregated state has been elucidated. Research should focus on the discovery of novel molecules that can be used in the treatment of AD. Thus, there is hope that the menace of AD can be fully

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eradicated in the near future, considering the repertoire of molecules that have shown potent effects against the fibrillation process of the A peptide.

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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS The authors are thankful for the facilities at AMU, Aligarh and KAU Jeddah. The financial support from the Council of Scientific and Industrial Research in the form of project No. 37(1365)/09/ EMR-II is gratefully acknowledged. The author would also like to thank the facilities provided by DSR and KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia. LIST OF ABBREVIATIONS

ELISA

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Enzyme-Linked Immunosorbent Assay

AFM

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Atomic Force Microscopy Epigallocatechin Gallate

FA

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Ferulic Acid

[25] [26]

[9]

[10] [11] [12] [13] [14] [15]

[27] [28]

[29]

[30]

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