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REVIEWARTICLE

Current Drug Metabolism, 2017, 18, 808-813

ISSN: 1389-2002 eISSN: 1875-5453

Exploration of Various Proteins for the Treatment of Alzheimer’s Disease

Current Drug Metabolism

Impact Factor: 2.659

The international journal for timely in-depth reviews on Drug Metabolism

BENTHAM SCIENCE

Badar ul Islam1, Syed Kashif Zaidi2, Mohammad Amjad Kamal3,4 and Shams Tabrez3,* 1 Department of Biochemistry, J. N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, India; 2 Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 3King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 4 Enzymoics, 7 Peterlee Place, Hebersham, NSW, Australia

ARTICLE HISTORY Received: September 12, 2016 Revised: October 06, 2016 Accepted: November 11, 2016

Abstract: Background: Alzheimer’s disease (AD) is an irreversible multifaceted neurodegenerative disorder that gradually degrades neuronal cells. It is the most frequent cause of memory loss and dementia in elderly individuals worldwide. The extracellular deposition of beta amyloid (A), intracellular neurofibrillary tangles (NFTs) retention, neuronal decline and neurotransmitter system derangement are the patho-physiological marker of this devastated disease.

Pe N rs ot on Fo al rD U s is e tri O bu nl tio y n

Current Drug Metabolism

808

DOI: 10.2174/1389200218666170203110135

Objective: In view of limited treatment option and their success rate, there is an urgent need to explore the vast array of proteomes for the management of AD. These proteins could be therapeutically targeted to prevent the progression of this disease. In the present review, we tried to uncover several proteins that could be exploited in AD therapeutics. Conclusion: Based on our article, we conclude that proteome based AD treatment needs more refinements and approaches to achieve the desired success rate.

Keywords: Alzheimer’s disease, amyloid beta, amyloid precursor protein, apolipoprotein, tau, therapeutics. 1. INTRODUCTION A multifactorial neurodegenerative disease (Alzheimer’s) gained interest among researchers for the past several years due to its worldwide etiology [1]. It is the most common form of dementia characterized by neuronal dysfunction and apoptosis that results in memory decline and impaired cognitive functions. About 36 million people across the globe are affected by this disorder and this number is expected to reach up to 114 million by 2050 [2, 3]. AD is categorized into early onset or familial (1-6%) and sporadic (>90%) [4]. Its multifaceted pathophysiology includes enhanced retention of amyloid beta (A) plaque around neuronal cells and neurofibrillary tangles formed by hyper-phosphorylated tau-related microtubule inside cells [5]. Some other disturbed mechanisms like calcium release, persistent oxidative imbalance, mitochondrial and mitotic dysfunction, hormonal disparity and inflammation are also believed to participate in AD pathogenesis. The proteasome system is the main clearance machinery for hyper-phosphorylated tau protein which gets blocked by A oligomers and plaques [6]. As a result, intracellular Ca2+ concentration gets disturbed which activates various inflammatory cascades, thereby promote neuronal dysfunction [7, 8]. Different hypotheses for AD pathogenesis have been put forwarded in literature which includes amyloid [9], glutamatemediated or glutamatergic [10], oxidative imbalance [11], inflammatory-mediated [12], acetylcholine-mediated or cholinergic [13] and metal-based [14]. The complex mechanisms involved in AD progression restrain the actual beneficial effect associated with any anti-Alzheimer drug. Till date, memantine, and four other cholinesterase inhibitors are approved by the US-FDA (Food and Drug Administration) for AD management. However, these drugs were unable to divert the route of the disease rather they just provide symptomatic effects. Therefore, the need of the hour is to find out novel and sophisticated therapeutic alternatives. In the present review, we focus on the *Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; E-mail: [email protected]

different proteins that could be therapeutically targeted to decipher the mysteries of AD puzzle in clinical perspectives. 1.1. Amyloid Precursor Protein (APP) Amyloid precursor protein is a type I transmembrane protein. It is produced in the endoplasmic reticulum (ER) as an antecedent for A and other peptides [15]. Post-translation, it is extensively altered via glycosylation followed by phosphorylation at some residues inside the cytoplasmic domain [16]. In this domain the interaction with various cytoplasmic proteins took place which aids in transport to different locations [17]. In amyloidogenic pathway, APP is cleaved by and -secretase enzymes whereas in non-amyloidogenic pathway, cleavage is carried out by - and -secretase enzymes (Fig. 1). The soluble APP fragment has been noted for neuroprotective features and signaling properties [18, 19]. Immunocytochemical studies revealed the locations of APP from the ER to lysosomes and autophagosomes [20]. Both full-length and fragmented APP exist at several unusual locations viz. nucleus [21], the ciliary root of retinal photoreceptor cells [22], mitochondria [23], and cytoplasm [24]. APP intracellular domain (APP fragment) can either enter the nucleus alone or in combination with Fe65 and APP binding protein [21]. This localization mode suggests a novel target that could aid in AD therapy. Other widely used strategies for AD therapy are the prevention of A generation, improvement in proper APP processing through inhibition of -, - or -secretase enzymes [25, 26]. 1.2. Amyloid Beta (A) Amyloid beta peptides are formed by the action of various secretase enzymes which lead to the formation of amyloid plaques [27]. Numerous studies demonstrated lower A42 density in cerebro spinal fluid (CSF) of AD patients [28, 29]. This notion is not clearly understood but it is believed that A42 confiscation to plaques is the main reason behind the reduced clearance of A into CSF [30]. On the other hand, Creuztfeldt-Jakob disease patients also have decreased levels of A clearance but they did not have any amyloid plaque deposition [31]. Hence, the decreased clearance of A is believed to be due to the different mechanisms that take place in various diseases. A recent study provided a notion that

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NON-AMYLOIDOGENIC PATHWAY a-Secretase

g-Secretase

P3 Peptides

Amyloid Precursor Protein (APP)

b-Secretase

g-Secretase

Amyloid Beta (Ab) monomers

Ab Oligomers

Ab Fibrils

Ab Plaques

AMYLOIDOGENIC PATHWAY

Fig. (1). Amyloidogenic and non-amyloidogenic pathway depicting APP cleavage by secretase enzymes.

employing somatostatin or its analogs to target neprilysin could be a good therapeutic approach in AD therapy. RAGEmediated active transport is the target of interest for the scientists as it transports A across the blood-brain barrier and aid in their deposition. Hence the use of RAGE inhibitors is considered as another therapeutic option in AD therapy. One of RAGE inhibitors (PF-04494700) has successfully completed phase 2 trials. Different monoclonal antibodies have the ability to bind A and aid in their clearance via microglial phagocytosis [59]. Solanezumab (LY2062430), a humanized monoclonal antibody against A16-24, binds with soluble A [60] whereas gantenerumab (R1450, a monoclonal antibody against A111) and crenezumab (humanized monoclonal antibody against A40/A42) have been reported to decrease cerebral A through microglial phagocytosis [61, 62].


decreased A42 clearance in AD patients is most probably due to the accumulation of A42 monomers into oligomers that results into epitope camouflaging accompanied by conformational alterations and making them inaccessible to antibodies [32]. Furthermore, this assumption is supported by the oligomerization of A42 in the brain parenchyma of AD patients. The possible A targeting approaches are listed below: Reducing A Production: It can be achieved either by the activating -secretase or inhibiting - and -secretase enzymes. Arresting A Oligomerization or Fibrillization: A peptides have the ability to self-aggregate that leads to the formation of oligomers, protofibrils, fibrils and finally A plaques [33, 34]. A vast array of molecules has been recognized that could either arrest A aggregation and fibrillogenesis or hinder A toxicity. Congo red (A fibril binding dye) has been reported to inhibit fibril generation along with their beneficial effect on neurotoxicity [35, 36]. Other compounds such as sulfonated anions, sulfonated dyes (benzofuran-type compounds) and amphiphilic surfactants (di-C6-PC and di-C7-PC) have also been reported for A inhibiting potential [37-39]. One study reported clearance of amyloid plaque by active immunization with A (AN 1792) in AD patients [40]. Tramiprosate (glycosaminoglycan) arrest the A oligomerization and fibril formation by interacting with A monomers while bapineuzumab (humanized monoclonal antibody against A1-5) interact with both soluble and fibrillar forms of A that decreases amyloid load in transgenic mice [41-43]. Another compound ELND005 or scylloinositol also inhibits A oligomerization by reducing soluble A, hence reverses the cognitive decline in transgenic mice [44]. Colostrinin (a proline-rich peptide) has been reported for its anti-aggregation property that results in the dissolution of pre-formed fibrils [45]. Recently, several new peptides with anti-aggregation potential have been synthesized [46]. An actin-binding protein, gelsolin plays an essential role in the assembly and disassembly of actin filaments and is extracellularly found in CSF and plasma and intracellularly in mitochondria and cytosol [47]. It has the ability to hamper A fibrillization and helps in the dissolution of preformed A fibrils, which increases its clearance [48]. Increasing A Clearance: Several proteases, such as angiotensinconverting enzyme (ACE), insulin degrading enzyme (IDE), cathepsin B, metalloproteinase 9, neprilysin and plasmin, play a major role in the digestion of A plaques and their decline may lead to retention of A in AD patients [49-51]. ACE has been reported to notably arrest A aggregation, retention, and cytotoxicity [52]. IDE is expressed in almost all tissues but greatly in testis, brain, liver and muscle and has A digesting capability [53-55]. Therefore, strategies that could increase the expression and activity of IDE could also be exploited as a potential approach for AD therapy. Cathepsin B (a cysteine protease), appreciably decreases A deposition through degradation of A1-42 at C-terminal and believed to reduce its level in AD brain [56, 57]. Somatostatin, a peptide hormone, modulates the A removal via neprilysin activation [58]. Therefore,

1.3. Tau Protein Tau is a microtubule-associated protein, commonly expressed in neurons, where it primarily takes part in microtubule stabilization (comprising nucleation, growth, and bundling), thereby regulates functional organization of the neuronal cells [63]. C-terminal end of tau protein contains microtubule-binding domain that is involved in the polymerization and stabilization of microtubules [64]. Whereas N-terminal is composed of highly acidic amino acids followed by proline-rich area. This domain is involved in the interaction between cytoskeleton and plasma membrane [65]. Phosphorylated tau interacts with microtubules with reduced affinity resulting in the instability of microtubules. This reduction in microtubule stability leads them into filamentous and non-filamentous aggregates that convert into neurotoxic NFTs and neuritic plaques at later stage [66]. The focal point of AD pathogenesis is tau hyperphosphorylation that causes microtubule instability [67]. Tau targeting strategies are depicted in Fig. (2) and are also listed below: Preventing Tau Phosphorylation: Kinase blocking is one of the convincing strategy to prevent tau phosphorylation. Various tau kinases capable of phosphorylating tau are cyclindependent protein kinase 5 (cdk5), glycogen synthase kinase 3 (GSK-3), stress-activated protein kinase (SAPK), microtubule affinity-regulating kinase (MARK), eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2), dualspecificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A), A-kinase anchor protein 13 (AKAP-13) and cAMP-dependent protein kinase (PKA) have been listed in literature [68-70]. Most studies reported lithium as the main blocker of GSK-3 however, several other compounds such as sodium valproate, flavopiridol, aloisines, aminothiazole ARA014418, pyrazolopyridines and pyrazolopyrazines have also been reported for GSK-3 blocking activity. Likewise, cdk5 inhibitors like indirubins, purine olomoncine, aloisines and flavopiridol are also considered for this purpose [69, 71]. Moreover, several important signaling pathways are actively regulated by the kinases, therefore one should consider the possible side effects caused by the use of kinase blockers [72,

810 Current Drug Metabolism, 2017, Vol. 18, No. 9

Islam et al. Tau Targeting Strategies

Block tau oligomerization or aggregation by the use of

Prevention of microtubule destabilization by the use of

Prevention of tau phosphorylation 1. Blockage of various kinases (cdk5, GSK-3b, SAPK, MARK, etc.) 2. Activation of phosphatases by drugs such as metformin and sodium selenite

1. Paclitaxel

1. Tau-binding drugs such as lansoprazole and astemizole

2. Epothilone D 3. Neuropeptides such as NAP and D-SAL

Increasing tau clearance

Increasing tau digestion 1. Hsp90 inhibitors such as curcumin

2. Methylene blue

1. Immunological-based approach such as use of monoclonal antibodies against phosphorylated tau

3. Natural phenolic compounds (hydroxytyrosol, oleuropein, oleurpein aglycone, etc.)

Fig. (2). A representative diagram highlighting strategies for tau-targeting.

Table 1.

Management of AD through various protein targeting and their molecular participants. Strategies

Participants


Targeted protein Amyloid precursor protein (APP)

Amyloid beta (A)

Tau protein

References

Prevention in amyloid beta (A) generation.

Inhibition of - or -secretase enzymes.

[25, 26]

Improvement in proper APP processing.

Inhibition of -, - or -secretase enzymes.

[25, 26]

Reduction in A production.

Activation of -secretase or inhibition of - and -secretase enzymes.

[30, 32]

Arresting A oligomerization.

Tramiprosate, ELND005 and colostrinin.

[41, 44-45]

Arresting A fibrillization.

Congo red, gelsolin, bapineuzumab and amphiphilic surfactants.

[35, 37-39, 42, 43, 48]

Increase in A clearance via digestion of A.

Angiotensin-converting enzyme, insulin degrading enzyme, cathepsin B, metalloproteinase 9, neprilysin and plasmin.

[49-51]

Increase in A clearance via neprilysin activation.

Somatostatin.

[58]

Increase in A clearance via active transport.

RAGE inhibitors.

[59]

Increase in A clearance via microglial phagocytosis.

Solanezumab, gantenerumab and crenezumab.

[61, 62]

Prevention in tau phosphorylation by kinase inhibitors.

Lithium, sodium valproate, flavopiridol, indirubins, purine olomoncine, aloisines etc.

[69, 71]

Prevention in tau phosphorylation by phosphatase activators.

Metformin, sodium selenite and memantine.

[74, 75]

Reduction in microtubule destabilization.

Paclitaxel, epothilone D, and neuropeptides.

[76-78]

Prevention in tau oligomerization/aggregation.

Lansoprazole, astemizole, methylene blue and natural phenolic compounds.

[79-84]

Acceleration in tau digestion.

Hsp90 inhibitors.

[86, 87]

Increase in tau clearance.

Monoclonal antibodies against phosphorylated tau.

[89, 90]

73]. Another strategy to dephosphorylate tau is the activation of protein phosphatases. The key enzyme involved in taubased dephosphorylation is protein phosphatase 2A (PP2A), thus its activators are believed to have therapeutical potential in AD treatment. Drugs, such as metformin and memantine have been reported for PP2A activating properties [74, 75]. On the other hand, sodium selenite (Ve-015), a PP2A activator, is under clinical investigation. Reduction in Microtubule Destabilization: Paclitaxel (a strong anticancer drug), is reported for microtubule stabilization poten-

tials, such as improvement in microtubule density, motor function, and axonal transport. Another compound, epothilone D has also been noted for microtubule stabilization effects besides blood-brain barrier clearance potential [76]. Neuropeptides, such as NAP and D-SAL, have also been documented for boosting effect on microtubule stabilization [77, 78]. Blocking Tau Oligomerization/Aggregation: One of the important tau-based AD treatment approaches is to find out the compounds that could block tau interaction and NFT deposition. Tau-binding drugs, such as lansoprazole and astemizole, are

Exploration of Various Proteins for the Treatment of Alzheimer’s Disease [7]

[8] [9] [10] [11]

[12] [13]

[14]

CONCLUSION In view of the current article and above-mentioned literature, we emphasize the exploitation of various proteins and their novel inhibitors for the clinical treatment of AD. The pathogenesis of AD is highly complex and several factors and signaling mechanisms actively participate in it. FDA-approved treatments for AD fail to stop or slow-down disease progression and are related to adverse side effects that decrease patient interest to therapy. Hence, its treatment still needs new refinements and approaches for novel targets in search to achieve complete endeavor.

[15]

[16]

[17]

[18]

[19]

[20]

CONSENT FOR PUBLICATION Not applicable.

CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS The authors gratefully acknowledge the research facility provided by the Aligarh Muslim University, Aligarh, India and King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia. Thanks are also due to Mohammad S Gazdar (Librarian, KFMRC) for providing assistance with the literature.

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indirectly helpful in reducing tau-tau interactions thereby arresting tau oligomerization/aggregation [79]. Methylene blue has been documented for various effects that include prevention of tau interactions, amyloid aggregation, acetylcholine esterase inhibition, reduction in oxidative stress, improvement in electron transport and mitochondrial damage aversion [80-83]. Daccache et al. [84] reported naturally occurring phenolic compounds (hydroxytyrosol, oleuropein and its derivative oleuropein aglycone) with tau arresting properties [84]. Accelerating Tau Digestion: Tau breakage is also considered as a promising treatment option against AD pathogenesis. Chaperones, like Hsp90, involved in the prevention of tau breakage besides its role in proper folding of denatured proteins [85]. Curcumin (Hsp90 inhibitors) has also been reported for tau breaking potential [86, 87]. However, the only concern related with chaperone blocking is the probable intrusion in their main activity may cause adverse effects. Increasing Tau Clearance: Immunological based approach for clearance of tau and its related fibrils receives interest lately [88]. Scientific studies reported beneficial effects in tau transgenic mice when they were passively immunized with monoclonal antibodies against phosphorylated tau [89, 90]. This suggests a potential of immune based approach for the AD treatment. We have also summarized various protein targeting approaches in the Table (1).


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