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REVIEW ARTICLE Multiple Targets for the Management of Alzheimer’s Disease

Syed Sayeed Ahmad1, Salman Akhtar1, Qazi Mohammad Sajid Jamal2, Syed Mohd. Danish Rizvi3, Mohammad A. Kamal4,5,6, M. Kalim A. Khan1 and Mohd. Haris Siddiqui1*

1Department of Bioengineering, Integral University, Lucknow 2Department of Health Information Management, College of Applied Medical Sciences, Buraydah Colleges, Al-Qassim, Kingdom of Saudi Arabia 3Department of Biosciences, Integral University, Lucknow, India 4King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia 5Enzymoics, 6Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia

Abstract: AD is a progressive and irreversible neurodegenerative disease and the most common cause of in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In A R T I C L E H I S T O R Y sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of Received: May 27, 2016 AD successfully. Currently, there are several medicines for the treatment of AD under survey like Revised: July 27, 2016 Accepted: September 22, 2016 Galangin, Cymserine, Tolserine, Bisnorcymserine and . The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of DOI: 10.2174/18715273156661610031658 AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the 55 progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

Keywords: Alzheimer’s disease, AChE, Beta-secretase, beta amyloid.

INTRODUCTION Organization, it has been observed that about 18 million people worldwide have been suffering from AD. It has been Alzheimer's disease (AD) was first described and named estimated that this figure will reach to approximately 34 by German psychiatrist and pathologist Alois Alzheimer in million by 2025. Hauser and colleagues were the first to 1906 [1]. AD is the most typical cause of dementia in the report that the incidence of seizures in patients with AD was aging people [2]. It is a progressive, neurodegenerative 10-fold increase as compared to the reference population [3]. pathology that primarily affects the elderly population, and is According to the World Health Organization assessment, estimated to account for 50 to 80 % of dementia cases in about three-quarters of the 1.2 billion elders will be living in persons over 65 years of age. But it is not just a disease of low- and middle-income countries by the year 2025. old age, since up to 5 percent of people with the disease have Dementia prevalence is high (above 5%) in most Asian and early onset Alzheimer's, which often appears when someone Latin American countries, according to the Age-adjusted is in their 40s or 50s. According to the World Health estimates. However, prevalence rates of dementia seem to be lower (1-3%) in India and sub-Saharan Africa [4]. *Address correspondence to this author at the Department of Bioengineering, Faculty of Engineering, Integral University, Pin Code: 226026, Lucknow, Cognitive dysfunction, primarily memory losses are the India; Tel: + 918604444786; E-mail: [email protected] main symptoms associated with this disease. Other features

1871-5273/16 $58.00+.00 © 2016 Bentham Science Publishers 2 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 Ahmad et al. associated with the later stages of AD include language manifestations are wandering, irritability and labile affect, deficits, depression, behavioral problems, including agitation, leading to crying, outbursts of unpremeditated aggression, or mood disturbances and psychosis. The etiology of AD is still resistance to care giving [16]. not clear. A lot of researches have been undertaken in recent During the final stages, the patient is completely years and concluded with some strong hypotheses. Some of dependent upon caregivers. AD is of major concern all over them are hypothesis, Amyloid cascade the world due to a number of factors, including (i) an aging hypothesis, Tau hypothesis, Oxidative stress hypothesis, population (ii) increasing life span and (iii) lack of effective Zinc dyshomeostasis hypothesis and Calpain-cathepsin pharmacotherapy option. People with AD will ultimately not hypothesis [5-10]. Current medication for AD includes use be able to perform even the simplest tasks independently; of AChE inhibitors such as (Aricept), muscle mass and mobility deteriorate to the point where they (Exelon), and (Razadyne, formerly are bedridden and unable to feed themselves. The cause of called Reminyl) [11]. death is usually an external factor, such as infection of pressure There are many challenges related to the study of the ulcers or pneumonia, not the disease itself [16] (Fig. 1). neuropathologic correlates of cognitive impairment in the elderly. An autopsy is required for definitive AD diagnosis, yet autopsy rates are generally low and autopsy inevitably confers a selection bias. Furthermore, clinicopathologic correlation (CPC) studies rarely are a random sample of the population and clinic- and hospital-based CPCs are subject to other potential biases [12]. The existence of persons without dementia with some AD neuropathologic changes is therefore not problematic. It is expected that many persons die with brains that exhibit AD neuropathologic change in the preclinical phase of AD; indeed, the data support the modeled expectations [13, 14]. Oxidative stress has been proposed as a pathogenic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Reported evidence of oxidative stress in AD includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids [15]. Available drugs targeting dementia are largely indicative towards temporary benefits of these medications that basically work on making available to its cognate receptor by inhibiting acetyl-cholinesterase. Few medications following this path include donepezil, galantamine or rivastigmine. Although many candidate drugs Fig. (1). Different Stages of Alzheimer’s disease. known to possess a distinct pharmacological mechanism failed to prove beneficial to humans in early clinical trials when tested in neurobiological models of AD delivering AGGREGATION OF BETA AMYLOID negative outcome. This review, recapitulates the available evidence on the new therapeutic approaches that target In 1991, the amyloid hypothesis postulated that amyloid and neurotransmitter in the AD focusing on extracellular (Aβ) deposits are the fundamental pharmaceutical compounds that have been approved by cause of the disease [19, 20]. Support for this postulate FDA. comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with Stages of Alzheimer's the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least In people with AD, the increasing impairment of learning the earliest symptoms of AD by 40 years of age [21, 22]. and memory eventually leads to a definitive diagnosis. In a Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 small percentage, difficulties with language, executive amino acids that are crucially involved in Alzheimer's functions, perception (agnosia), or execution of movements disease as the main component of the amyloid plaques found (apraxia) are more prominent than memory problems. in the brains of Alzheimer patients. The peptides result from Language problems are mainly characterized by a shrinking the amyloid precursor protein (APP), which is cleaved by vocabulary and decreased word fluency, leading to a general beta secretase and gamma secretase to yield Aβ. The impoverishment of oral and written language. In this stage, amyloid plaques are toxic to nerve cells. The other protein the person with Alzheimer's is usually capable of implicated in Alzheimer's disease,tau protein, also forms communicating basic ideas adequately [16-18]. During the such prion-like misfolded oligomers, and there is some moderate phase, memory problems worsen, and the person evidence that misfolded Aβ can induce tau to misfold [23, may fail to recognize close relatives. Behavioural and 24]. APP is part of a protein family in mammals with two neuropsychiatric changes become more prevalent. Common homologous proteins, APP like protein 1 (APLP1) and 2 Multiple Targets for the Management of Alzheimer’s Disease CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 3

(APLP2). APP itself is a transmembrane protein that has 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme both cytoplasmic and extracellular cleavage products that are that in humans is encoded by the BACE1 gene. BACE1 (Fig. 3) relevant in AD. APP is initially cleaved via α-secretase or is an aspartic-acid protease important in the formation of β-secretase, which forms normal or pathological products myelin sheaths in peripheral nerve cells [29, 30]. Beta- (Fig. 3). Therefore, both α-secretase agonists and β-secretase secretase (BACE) is the major protease of the amyloid antagonists could act as Alzheimer therapeutics. Whether α- precursor protein pathway which generates and accumulates secretase or β-secretase cleaves APP, there is an intracellular Aβ in the brain. As high level of Aβ in the brain is directly release of amyloid precursor protein intracellular domain associated with AD pathogenesis, BACE has been (AiCD). Following α or β cleavage, γ-secretase cleavage considered as a potential therapeutic target for AD for the yields extracellular p3 or Aβ, respectively. β- Secretase1 in development of novel inhibitor drugs for the reduction of the particular has been found to have increased activity in Aβ amount in the brain [31]. Amyloid β (Aβ) plaques are Alzheimer’s patients, as well as those with mild cognitive one of the most prominent histological features found in the impairment that went on to develop AD [25] (Fig. 2). AD brain and supposed to play a crucial role in the pathology of AD [32, 33].

Fig. (3). Apo structure of Beta-secretase [PDB ID: 1W50].

Fig. (2). 3- Dimensional structure of Alzheimer’s Amyloid beta [PDB id: 2BEG]. Endothelial cells of the blood-brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific The deposition of amyloid in brain tissue in conjunction transporters such as P-glycoprotein. The blood-brain barrier with neurodegenerative diseases involves the formation of is responsible for negligible bioavailability of many intermediate species, with lower molecular mass and a neuroprotective drugs. In Alzheimer's disease, current deviating structure than mature amyloid fibrils, termed treatment approaches include inhibitors of BACE-1 (β-site of oligomers [24]. Small proteins like amyloid beta (Aβ) amyloid precursor protein cleaving enzyme), a proteinase monomers are related to aggregation of insoluble fibrils. Small angle neutron scattering (SANS) is a nondestructive generating neurotoxic β-amyloid. ADmouse model shows method to observe the aggregation process in solution [26]. that BACE-1 is upregulated at the blood-brain barrier Sequences rich in glutamine (Q) and asparagine (N) are compared to healthy controls. We therefore suggest a critical intrinsically disordered in monomeric form, but can role for BACE-1 at the blood-brain barrier in β-amyloid aggregate into highly ordered amyloids, as seen in Q/N-rich generation and in vascular aspects of Alzheimer's disease, prion domains (PrDs). Amyloids are fibrillar protein particularly in the development of cerebral amyloid aggregates rich in β-sheet structures that can self-propagate angiopathy [34]. BACE1 is primarily expressed in neurons in through protein-conformational chain reactions [27]. The the brain. β-Secretase inhibitors work to block the first most common isoforms are Aβ40 and Aβ42; the longer form is cleavage of APP inside of the cell, at the endoplasmic typically produced by cleavage that occurs in theendoplasmic reticulum while γ-Secretase inhibitors work to block the reticulum, while the shorter form is produced by cleavage in second cleavage of APP in the cell membrane and would the trans-Golgi network [28]. then stop the subsequent formation of Aβ and its toxic fragments and selective Aβ42 lowering agents modulate γ- Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions. The β -secretase called BACE1 is a Beta-secretase 1 (BACE1), also known as beta-site membrane-associated protease that initiates the generation of amyloid precursor protein cleaving enzyme 1, beta-site APP amyloid β-protein (Aβ), a key event in Alzheimer’s disease. cleaving enzyme 1, membrane-associated aspartic protease 4 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 Ahmad et al.

Fig. (4). Working of beta- secretase in the formation of Amyloid beta and Plaque formation.

AMYLOIDOGENIC PATHWAY IN ALZHEIMER AChE is a 537 amino acid-long peptide monomer capable of hydrolyzing acetylcholine at a rate of 250000 molecules a Amyloidogenic pathway is the result of a mutation that second. It is composed of a 12-stranded mixed beta sheet replaces the normal pathway. In normal pathway !- secretase surrounded by 14 alpha helices giving it a tertiary structure acts on the APP followed by "-secretase forming harmless similar to many hydrolases [53]. The active site is located in p-3 peptide but the amyloidogenic pathway involves a deep gorge that stretches halfway into the protein. The breakdown of APP by #-secretase followed by "-secretase gorge itself is composed of 14 aromatic residues that help and results in the formation of amyloid beta plaque [35, 36]. stabilize the quaternary ammonium ion of acetylcholine. #-ssecrets have been a promising target for developing novel anti-Alzheimer drugs [37]. The amyloid-beta (Aβ) and tau Acetylcoholinesterase (AChE, EC 3.1.1.7), is a serine proteins have been the two leading targets thought to be the hydrolase. Silman and Sussman have described ‘structure- causative agents leading to Alzheimer’s disease (AD) [38-42]. function relationship’ for AChE and reported that the The overall amyloidogenic pathway is depicted in Fig. (4). enzyme was derived from a large family of proteins that, jointly, share a common α/β fold [54]. Such protein enzymes that are esterases, lipases and proteases, along with non- ROLE OF RAGE IN ALZHEIMER’S DISEASE enzymatic proteins that operate as adhesion molecules and The receptor for advanced glycation end products pro-hormones [55, 56]. Such proteins comprise enzymes that (RAGE), which belongs to the immunoglobulin superfamily, are esterases, lipases and proteases, along with non- was first identified and described in terms of its ability to enzymatic proteins that operate as adhesion molecules and bind advanced glycation end products (AGEs). Ligands that pro-hormones. have been found to be recognized by RAGE include AGEs, amyloid #-peptide, DNA binding protein, high mobility group box-1 (HMGBl)/amphoterin, and S100/calgranulins [43-47]. Binding of AGEs and A# to RAGE has been reported to stimulate activation of transcription factor NF-$B which in turn induces the release of various cytokines such as IL- 1, IL-6, TNF-!, endothelin-1, and tissue factor [48- 50]. Activation of NF-$B was found to be involved in neuronal plasticity and the cellular response to neurodegeneration [51]. The A#-RAGE interaction at the BBB not only results in neurovascular stress and expression of proinflammatory cytokines (TNF-! and IL-6) but also leads to decreased cerebral blood flow by enhancing the secretion of endothelin-1 to induce vasoconstriction [52].

NEUROTRANSMITTERS IN ALZHEIMER’S DISE- Fig. (5). Structure of recombinant human ASE [PDB ID: 3LII]. Acetylcholine Neurotransmitters also known as chemical messengers, The structure of Acetylcholinesterase (Fig. 5) was first are endogenous chemicals that enable neurotransmission. determined by J.L. Sussman in 1991 by X-ray analysis. They transmit signals across a chemical synapse, such as a Multiple Targets for the Management of Alzheimer’s Disease CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 5 neuromuscular junction, from one neuron to another "target" MECHANISM OF AChE IN ALZHEIMER’S DISEASE neuron, muscle cell, or gland cell [57]. Neurotransmitters are During neurotransmission, ACh is released from the released from synaptic vesicles in synapses into the synaptic nerve into the synaptic cleft and binds to ACh receptors on cleft, where they are received by receptors on the target cells. the post-synaptic membrane, relaying the signal from the Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers are unknown, but more nerve. AChE, also located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh. The than 100 chemical messengers have been identified [58]. liberated is taken up again by the pre-synaptic nerve Acetylcholine is an organic chemical that functions in the and ACh is synthesized by combining with acetyl-CoA brain and body of many types of animals, including humans, through the action of choline acetyltransferase [66, 67]. as a neurotransmitter—a chemical released by nerve cells to send signals to other cells. Its name is derived from its Cholinergic hypothesis is the oldest one and it is still chemical structure: it is an ester of acetic acid and choline. promising in understanding AD for designing drugs. This Parts of the body that use or affected by acetylcholine are hypothesis proposed that degeneration of cholinergic referred to as cholinergic [59]. neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and The primary physiological role of AChE involves the other areas contributed significantly to the deterioration in termination of chemical transmission at cholinergic synapses and secretory organs by catalyzing the hydrolysis of the cognitive function seen in patients with AD. As it has been reported that AD is caused by multiple risk factors, hence, neurotransmitter acetylcholine, ACh, at a high turnover rate this hypothesis is modified by certain authors. AChE (2.5x104 molecules per second). A significant number of inhibitors are employed to reduce the rate at which ACh is roles have been attributed to AChE in diseases of high broken down, thereby increasing the concentration of ACh in scientific concern e.g. cancer [60]. Depending on their time- the brain and combating the loss of ACh caused by the death dependent concentration, mechanism of binding and use, inhibitors of AChE have been demonstrated to have efficacy of cholinergic neurons [68]. The mechanism of AChE is well illustrated in Fig. (6). (e.g., donepezil, rivastigmine and galantamine in AD; and in myasthenia gravis) [61] as well as toxicity (e.g. organophosphate and pesticides in health) TREATMENT OF AD [62]. At present, the mainstay of AD therapy are drugs that target neurotransmitter systems in the brain. AD primarily DISTRIBUTION ACETYLCOHOLINESTERASE damages glutamate and acetylcholine-producing neurons and their associated synapses, and this damage correlates AChE is found in many types of conducting tissue: nerve well with early cognitive symptoms of AD [69] and muscle, central and peripheral tissues, motor and sensory Acetylcholinesterase inhibitors help improve memory fibers, and cholinergic and noncholinergic fibers. The function and attention in AD patients by interfering with the activity of AChE is higher in motor neurons than in sensory breakdown of acetylcholine, thereby increasing the levels of neurons [63, 64]. AChE is also found on the red blood cell membranes, where different forms constitute the Yt blood the neurotransmitter at the synapse. Drugs that act to decrease the amount of Aβ protein in the brain have received group antigens [65]. the most attention due to the prominent pathogenic role

Fig. (6). AChE mechanism of action.

6 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 Ahmad et al.

Table 1. List of FDA approved drugs for the treatment of Alzeimers’s disease.

S. No. Drug Name Approved Year Brand Name Side Effects

1 2014 Namzaric Headache, constipation, confusion etc.

2 Rivastigmine 2000 Exelon Nausea, Vomiting, Loss of Appetite etc.

3 Galantamine 2001 Razadyne Nausea, Vomiting, Loss of Appetite etc.

4 Donepezil 1996 Aricept Nausea, Vomiting, Loss of Appetite etc.

5 1993 Cognex Liver damage, Nausea, Vomiting etc.

ascribed to Aβ in the AD literature [70, 71]. Another strategy amyloid plaque-associated protein, amyloid-beta peptide that has been attempted is by using drugs that promote the [78]. clearance of Aβ through active or passive immunization 3. Huperzine A (HupA) is a Lycopodium alkaloid [72]. Five medications are currently used to treat the isolated from the Chinese medicinal herb Huperzia serrata. It cognitive problems of AD: four areacetylcholinesterase is used for memory deficiency, and is greatly interesting as it inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is a N-Methyl-D-aspartate acts as a highly selective, reversible, and potent AChE receptor (NMDA) antagonist [73]. Advanced medical inhibitor. It is of 2 types – HupA and Hup B. Hup B is a imaging with computed tomography (CT) or magnetic naturalhomologue of HupA [76]. Huperzine B (HupB) has resonance imaging (MRI), and with single-photon emission been demonstrated as an effective and reversible inhibitor of computed tomography (SPECT) or positron emission AChE. HupB is less potent and selective than HupA, but it tomography (PET) can be used to help exclude other cerebral has higher therapeutic index and other positive benefits [79]. pathology or subtypes of dementia [74]. The U.S. Food and 4. Tolserine is a fourth generation Acetylcholinesterase Drug Administration (FDA) has approved the following inhibitor. It is used for the treatment of AD that is rapidly drugs to treat the symptoms of Alzheimer's disease. The absorbed through membranes and can also be applied detailed information about the drugs is summarized in Table 1 topically to the conjunctiva. It can also cross the blood-brain and the 2D chemical structure is shown in Fig. (7). barrier and is used when central nervous system effects are Donepezil, galantamine and rivastigmine are cholinesterase desired, as in the treatment of severe toxicity inhibitors. Memantine is an NMDA receptor antagonist, [79]. which works by regulating the activity of glutamate, 5. Galangin is a flavonoid that acts as an inhibitor of an important neurotransmitter in the brain involved in AChE. The effect of this dietary flavonoid was found on the learning and memory (http://www.alz.org/research/science/ of 7, 1, 2-dimethylbenz [a] anthracene (DMBA). alzheimers_disease_treatments.asp). It was found to inhibit the catabolic breakdown of DMBA, as measured by thin-layer chromatography, in a dose-dependent NEW THERAPEUTIC CANDIDATES FOR THE manner [77]. TREATMENT OF ALZEIMERS’S DISEASE 6. , a phenylcarbamate derivative of physostig- 1. Resveratrol (3, 4, 5-trihydroxystilbene) is a naturally only inhibits ACh but also modulates the amount of beta- occurring Phytochemical. It is present in red wine, grapes, mine, is a selective, non-competitive AChE inhibitor that not berries, chocolate and peanuts. Resveratrol contains amyloid precursor protein (APP) by reducing APP antioxidant, anti-inflammatory, anti-viral, and anti-cancer translation via interaction with the 5’- untranslated region of properties. It was isolated in 1940, and recognised for its the APP gene [76]. The phenserine is a novel cholinesterase potential therapeutic role in reducing the risk of inhibitor. Phenserine (0.025-0.40 microM) inhibited the neurodegeneration, and Alzheimer's disease (AD) in activity of human erythrocyte AChE in a concentration- particular. Resveratrol has demonstrated neuroprotective dependent fashion, the IC50 was 0.0453 microM [80]. effects in several in vitro and in vivo models of AD. Apart 7. Naringenin The beneficial effect of naringenin on from its potent antioxidant and anti-inflammatory roles, improvement of learning and memory was evaluated in an evidence suggests that resveratrol also facilitates non- Alzheimer's disease rat model. Naringenin pretreatment of amyloidogenic breakdown of the amyloid precursor protein Aβ-injected rats also lowered hippocampal malondialdehyde (APP), and promotes removal of neurotoxic amyloid beta (MDA) with no significant effect on nitrite and superoxide (Aβ) peptides, a critical step in preventing and slowing down dismutase (SOD) activity in addition to lowering apoptosis. AD pathology [75]. These results suggest naringenin pretreatment attenuates Aβ- 2. Bisnorcymserine is a derivative of drug Cymserine, induced impairment of learning and memory through which is related to . Bisnorcymserine is highly mitigation of lipid peroxidation and apoptosis and its selective for BuChE [76]. It has potential to improve the beneficial effect is somewhat mediated via estrogenic symptoms of patients with severe AD [77]. It lowers the pathway [81]. Multiple Targets for the Management of Alzheimer’s Disease CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 7

O NH2

O CH3 H N O H3C N O CH3 N H CH3 CH3 Memantine Rivastigmine

HO Galantamine O

N

O N

O Donepezil NH2 Tacrine

Fig. (7). Structure of FDA approved drugs for the treatment of Alzeimers’s disease.

8. Cymserine acts as a reversible BuChE inhibitor and onset of AD. Some of the major antibodies are discussed useful for treating AD without producing side effects like below: , lacrimation and salivation. A number of cymserine derivatives have been developed and several of its analogues 1. Bapineuzumab have been tested in animals. These were found to increase Bapineuzumab, a humanized monoclonal antibody brain ACh levels, and did not produce tropic effects. currently in Phase III clinical trial is designed to decrease Furthermore, these were found to reduce the levels of plaque formation and encourage clearance of Aβ being amyloid precursor protein and amyloid beta, the known specific to the N-terminus of the amyloid β (Aβ) protein. biomarkers for the development of AD [82-84]. Bapineuzumab binds to the soluble and fibrillar forms of Aβ 9. Aptiom (Eslicarbazepine acetate) has been authorized and is well-tolerated at doses less than 2mg/Kg [88] by the Food and Drug Administration as an add-on drug to decreasing total brain Aβ load [89]. help treat adults with partial epileptic seizures [85]. Eslicarbazepine acetate is absorbed to at least 90% from the 2. Aducanumab gut, independently of food intake. It is quickly metabolised to eslicarbazepine, so that the original substance cannot be Aducanumab (BIIB037) is a human recombinant detected in the bloodstream. Peak plasma levels of monoclonal antibody presently in phase III clinical trial. It is eslicarbazepine are reached after 2–3 (1–4) hours, and well reported to target Aβ soluble oligomers along with plasma protein binding is somewhat less than 40%. insoluble fibrils that settle down into the Aβ plaque in the Biological half-life is 10 to 20 hours, and steady-state brain of AD patients. Aducanumab treatment has been seen concentrations are reached after four to five days after the to slow down the clinical impairment in patients with mild start of the treatment [86]. AD in a considerable way [90]. It is well reported that one year of monthly intravenous infusions of aducanumab results 10. Fetzima is chemically known as levomilnacipran. It in reduction of Aβ in brain of patients suffering from might act as a potent inhibitor of BACE-1 and expected to prodromal or placid AD [91]. form the basis of a future therapy against AD. It is approved by Food and Drug Administration in July 2013. 3. Solanezumab and Crenezumab Levomilnacipran has recently been found to act as an inhibitor of beta-site amyloid precursor protein cleaving Solanezumab and crenezumab developed by Eli Lilly and enzyme-1 (BACE-1), which is responsible for β-amyloid Genentech respectively are the chief clinical antibodies plaque formation, and hence may be a potentially useful drug targeting Amyloid-β (Aβ). It has been tested in multiple in the treatment of Alzheimer's disease [87]. Phase III clinical trials for the prevention of Alzheimer's disease in susceptible individuals. These antibodies generally The detailed information about the above mentioned capture Aβ in the mid domain region forming Aβ-anti-Aβ compounds is summarized in Table 2 and their respective 2D complex crystal structure. The major exciting feature of chemical structure is shown in Fig. (8). solanezumab and crenezumab is that they differ in their immunoglobulin backbone i.e. IgG1 and IgG4 respectively NEW THERAPEUTIC ANTIBODY FOR THE [92, 93]. TREATMENT OF ALZHEIMER’S DISEASE 4. BAN2401 Active and passive immunotherapies are being developed to target AD. The neurotoxic species like mature Aβ fibrils BAN2401 is the humanized monoclonal antibody are considered as an important centre for development of developed by immunization of mouse with protofibrils antibody that identifies the ‘aggregation epitopes’ and thus, having arctic Aβ42 mutation thus remains in a prefibrillar helps in inhibition protein aggregation responsible for the setting rather than fibrillar. Due to its ability to selectively 8 CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 Ahmad et al.

Table 2. List of new therapeutic candidates for the treatment of Alzheimer’s disease.

S. No. Compounds Name IUPAC Name PubChem CID Molecular Formula

1 Resveratrol 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol 445154 C14H12O3

[(3aR,8bS)-8b-methyl-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]indol-7-yl] N- 2 Bisnorcymserine 71587645 C H N O (4-propan-2-ylphenyl)carbamate 21 25 3 2

(1R,9S,13E)- 1-Amino- 13-ethylidene- 11-methyl- 6-azatricyclo[7.3.1.02,7] 3 Huperzine A 5912039 C H N O trideca- 2(7),3,10- trien- 5-one 15 18 2

[(3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N- 4 Tolserine 9928397 C H N O (2-methylphenyl)carbamate 21 25 3 2

5 Galangin 3,5,7-trihydroxy-2-phenylchromen-4-one 5281616 C15H10O5

[(3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N- 6 Phenserine 192706 C H N O phenylcarbamate 20 23 3 2

7 Naringenin 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one 932 C15H12O5

[(3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N- 8 Cymserine 9907847 C H N O (4-propan-2-ylphenyl)carbamate 23 29 3 2

9 Aptiom [(5S)-11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl] acetate 179344 C17H16N2O3

(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1- 10 Fetzima 6917779 C H N O carboxamide 15 22 2

OH H HO N O N O H N H Resveratrol H OH Bisnorcymserine Huperzine A

N H CH3 O HO O N N O CH3 N O N H OH N O Tolserine H OH O CH3 Phenserine Galangin

OH H HO O N O N O N Cymserine OH O Naringenin NH2 Aptiom

N

O Fetzima

Fig. (8). Structure of new therapeutic candidates for the treatment of Alzeimers’s disease.

Multiple Targets for the Management of Alzheimer’s Disease CNS & Neurological Disorders - Drug Targets, 2016, Vol. 15, No. 10 9 bind, neutralize and eliminate protofibrils, BAN/mAb158 is ACKNOWLEDGEMENTS successfully being assessed in clinical Phase II trial [94]. The authors are thankful to Prof. S.W. Akhtar, The Hon’ble vice Chancellor, Integral University for providing 5. Gantenerumab necessary infrastructure facilities to complete this study. Gantenerumab is an untried fully human anti-amyloid beta monoclonal antibody with a elevated capacity to bind REFERENCES and confiscate beta-amyloid plaques in the brain. It generally targets the N-terminus and central portion of Aβ with high [1] Berchtold NC, Cotman CW. Evolution in the Conceptualization of binding affinity to cerebral amyloid plaques. It is presently Dementia and Alzheimer's Disease: Greco-Roman Period to the 1960s. 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