INTRODUCTION:

AD is a neurodegenerative disorder characterized by progressive loss of memory, decreases the cognitive function, physical function, and brain cell results in death. AD is one among the disease-causing dementia.¹AD is are classified into two categories – Late-Onset Alzheimer's Disease (LOAD), Early Onset Alzheimer's Disease (EOAD). LOAD occurs to the people of age above 65 years. EOAD happen to the people of age below 65 years. Familial Alzheimer's disease (FAD) associated with EOAD occurring at the period as early as 25 years.^2,50 Age and possession of the ε4 allele of the Apolipoprotein gene (APOE ε4) are the high-risk factors for most of the population. The factor responsible for EOAD or FAD is the presence of the mutation at three loci. One locus is related to the Amyloid Precursor Protein (APP), which is cleaved by two types of enzymes - β-secretase and γ-secretase.^{3, 4}

Mutations in APP leads to the abnormal cleavage of APP leading to the incorrect larger or smaller segment of Aβ, which further leads to the aggregation of these segments. Other two loci are related to mutations in the presenilin genes – PRES1 AND PRES2 account for EOAD (FAD).⁵The major pathophysiological hallmarks of AD are Neurofibrillary Tangles and Amyloid β Plaques. Depletion of Acetylcholine, excitotoxicity due to elevated glutamatergic transmission, oxidative stress and chronic inflammation due to damaged neurons are also pathophysiological factors for AD.⁶

These changes result in an aggregate of amyloidogenic peptides which forms into oligomers, which blocks the synaptic neurotransmission and then into amyloid plaques, it interferes with intracellular metabolic alterations leads to hyperphosphorylation of tau protein. Phosphorylated tau proteins aggregate to form neurofibrillary tangles which alter the intracellular metabolism which causes neuronal death.^7,8Treatments for AD are aimed to increases the cognitive or neuropsychiatric symptoms and neurotransmitter mechanisms; disease-modifying therapies are the agents to delay, prevent or slow down progression and targeting the pathophysiological mechanisms of Alzheimer's disease.⁹Pathogenesis of the Alzheimer's diseases shown in (figure 1)^{10, 51}.

Figure: 1 Pathogenesis of Alzheimer’s disease

SYMPTOMS^11-13,52

· Repetitive questions or conversations

· Misplacing personal belongings

· Forgetting events

· Poor understanding of safety risks

· Inability to manage finances

· Poor decision-making ability

· Failure to plan complex or sequential activities

· Inability to recognise faces

· Inability to use simple tools

· Speech, spelling, and writing errors

Targets for the therapy of AD:

Fig: 2Major targets in AD

Targeting amyloid β-peptide (Aβ):

A target of treatment of AD was shown in (figure 2)¹³. Aβ peptide, the primary constituent of senile plaques, signifies peptides of 36−43 amino acids that are crucially associated with AD and got from an amyloid precursor protein (APP) by the proteolytic cleavage of β-and γ-secretase.¹⁴ Aβ exists in the cerebrospinal fluid at low concentration and gives sustenance to immature neurons. Since imbalance in synthesis, catabolism, and transportation, Aβ aggregates and settles in brain tissue results in disease, triggering a cascade and death of neurons.^15,53It has been shown that Aβ may be the most dangerous as dissolvable oligomers in the beginning period of aggregation. The gene change of APP, presenilin-1 (PS-1) and presenilin-2 (PS-2), particularly that of PS-1, results in an expansion in Aβ, which is ended up being the fundamental explanation behind early-beginning AD^16,17. In this manner, it has been a problem area to postpone and mitigate AD to diminish Aβ development and deposition and to inhibit its aggregation.

Targets of anti-Aβ mAbs:

The lack of efficacy thus far with anti-Aβ mAbs may reinforce the case against the amyloid hypothesis of AD. However, encouraging results with some antibodies make it equally difficult to dismiss this hypothesis altogether.^18,54Neurotoxic species of Aβ is a soluble oligomer, is the main target for disease-modifying treatments, counting mAbs. Reducing fibrillary Aβ at the cost of augmenting soluble species could be harmful in transgenic mouse models, even mAbs target fibrillar and oligomers. In such a manner, the clearance of fibrillary Aβ on a PET is maybe not a basic objective of treatment but rather may happen as an epiphenomenon to the clearance of oligomers.¹⁹Bapineuzumab, Solanezumab, Gantenerumab are some anti-Aβ mAbs under clinical trial. Among the anti-Aβ therapeutic approaches, the most extensively developed is immunotherapy—specifically, administration of exogenous monoclonal antibodies (mAbs). Testing of mAbs are confusing results and failure, from the trials, have provided vital clues and information for the better treatment.^20,
21,55

Targeting cholinergic neurotransmitter:

Cholinergic synapse is a vital substance in brain required with cardiovascular activities, a direction of motility and sensation, the physiological procedure of learning and memory, etc.^22,56 It reported that AD regularly has weakening and a decrease in the cholinergic neuron, particularly in basal forebrain areas, hippocampus and neocortex.²³ Acetylcholine (Ach) is a one amongst the most important synapses in the brain and has the close connection to the cognition. Acetylcholine esterase (AchE) and choline acetyltransferase (ChAT) are critical enzymes catalysing hydrolysis and synthesis of Ach, individually.²⁴ The anomalous articulation of AchE and ChAT prompts the disorder of Ach synthesis and discharge, with the indications of declining acknowledgement function and memory issue.^25,57

Many treatments are to enhance the activity of the cholinergic neurons, by increasing the Ach synthesis and inhibiting the Ach degradation by Ach inhibitors etc. AchE are used predominantly for the treatment of cognitive problems, such as tacrine, donepezil, galantamine and rivastigmine.²⁶

Activation of α-Secretase:

The agonist of the α-secretase enzyme results to APP being processed by the non-amyloidogenic pathway, which reduces APP available in the amyloidogenic pathway.²⁷The outcome is dissolvable a peptide play role as a neuroprotector and stimulator of synaptogenesis. α-secretase activation provides an alluring methodology to the development of disease-modifying drugs.²⁸ Various compounds potentially able to trigger the non-amyloidogenic pathway, it includes Ach muscarinic receptor, serotonergic agonists, protein kinase C activators and glutamatergic^29,58. In any case, researchers have not discovered compounds able to modulate this pathway in animal models viable, and therefore very few such as Epigallocatechin gallate, Acitretin and Bryostatin 1 are the compounds have reached the clinical trial stages.^30-31

Inhibitors of Beta-secretase (BACE1):

the β-secretase enzyme is responsible for the amyloidogenic pathway to regulate APP. To develop inhibitors for β-secretase is challenging because it has more substrates like neuregulin-1 involved in myelination of the peripheral nerves.³²

Because of this reason, nonspecific enzyme inhibitions may result in adverse effects; the largest problem has to do with the enzyme's structure. It belongs to the aspartic protease class; these inhibitors must be a large, hydrophilic molecule; as such, it will not be able to cross BBB easily.^33-35 The scientist is examining various compounds with the aim of overcoming these obstacles and drug that will be effective against Alzheimer's disease. Recent studies indicate E2609 and MK-8931 are two inhibitors of β-secretase, these are effective at decrease levels (80-90%) in human CSF.^36-37

N-Methyl-D-Aspartate receptor:

Excessive and continuous Ca²⁺influx through the receptor in Alzheimer’s Disease patients because of increased inactivation of N-methyl-D-aspartate (NMDA) type glutamate receptors.³⁸For the normally functioning nervous system, Glutamate-mediated synaptic transmission is important, because it is a vital excitatory neurotransmitter in the brain.³⁹Excessive activation of the NMDA receptor with glutamate triggers the synthesis of free radicals and other enzymes that lead to the death of neuronal cells. Due to inappropriately release of glutamate is not eliminated properly, with the disruption of energy metabolism during acute and chronic neurodegenerative disorders.⁴⁰

Neuron becomes depolarised in this energetic compromised, depolarisation releases the mg²⁺block of NMDA receptor-coupled channels.⁴¹ Glutamate receptor stimulation is supposed to occur when ischemia and other neurodegenerative symptoms present in the brain. Hence, NMDA antagonist is therapeutically benefiting in the disorders like neuropathic pain, dementia and stroke.⁴²Memantine, Pethidine, levorphanol, tramadol and ketobemidone are the NMDA receptor antagonist.⁴³

TARGETING TAU PROTEINS:

Molecular pathology information has numerous lead analysts to the end that neurofibrillary tangle arrangement may be the fundamental driver of AD.⁴⁴. This theory is primarily founded in for accompanying perceptions: neurofibrillary tangles are absent in the normal brain, outside the hippocampal region; neurofibrillary tangles are intracellular; and the thickness of neurofibrillary tangles is straightforwardly related to the seriousness of dementia, in many investigations.

Therefore, anti-tau considered as another pathway to the treatment of AD.^45,59

Tau phosphorylation and aggregation inhibition:

High Tau phosphorylation and accumulation are triggers in the development of neurofibrillary tangles, which at long last lead to neuronal death. Tau hyperphosphorylation is reduced by restraining glycogen synthase kinase 3(GSK-3) is the enzyme mainly responsible for this process.^46-47 One conceivable remedial alternative for this case could be lithium, yet its efficiency in AD has not been assessed up until now, even though it has a demonstrated as a protective effect against the development of AD and preclinical information have since a long time ago turned out to be compelling in vitro. GSK-3 is additionally inhibited by PKC, which thus is by M1 receptor agonists, including acetylcholine, and recent studies have proven that such products can reduce Tau phosphorylation and aggregation, Tau aggregation blocking agents.^48-49

CONCLUSION:

AD is a chronic neurodegenerative disease, and the mechanism is poorly understood. Its pathological process is complicated and affected by multiple factors. Drugs for AD treatment on the current market mostly target on single molecules and temporarily improve symptoms. Novel drug are in the treatment of AD in multiple-pathway, multiple-targets and multi-levels and alternative hypothesis have been proposed to interpret the failure of the amyloidogenic prediction. These include the adaptive response hypothesis, stating that A may aggregate due to an adaptive response to chronic stress stimuli at the cerebral level. For example, LYSP has anti-AD effect by acting on the metabolism of free radicals, cholinergic, monoamine and amino acid neurotransmitter, APP and Aβ expression as well as by anti-apoptosis. So, for the novel therapies that act at the root of the disease process and will be able to stop the progressive accumulation of Aβ. Targeting Aβ production via inhibition of β-secretase, though a promising approach, but at present only a few compounds have been tested and undergone clinical trials. Another enzyme involved in Aβ oligomers production, i.e. β-secretase can also be targeted but the risk of toxicity associated with inhibition is hindering the use of such compounds for the treatment of AD patients.

CONFLICTS OF INTEREST:

All authors declare that they have no conflicts of interest.

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Received on 14.01.2019 Modified on 16.03.2019

Research J. Pharm. and Tech. 2019; 12(6):3073-3077.

DOI: 10.5958/0974-360X.2019.00521.3