Molecular drug targets and therapies for Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by normal memory loss and cognitive impairment in humans. Many drug targets and disease-modulating therapies are available for treatment of AD, but none of these are effective enough in reducing problems associated with recognition and memory. Potential drug targets so far reported for AD are β-secretase, γ-secretase, amyloid beta (Aβ) and Aβ fibrils, glycogen synthase kinase-3 (GSK-3), acyl-coenzyme A: cholesterol acyl-transferase (ACAT) and acetylcholinesterase (AChE). Herbal remedies (antioxidants) and natural metal-chelators have shown a very significant role in reducing the risk of AD, as well as lowering the effect of Aβ in AD patients. Researchers are working in the direction of antisense and stem cell-based therapies for a cure for AD, which mainly depends on the clearance of misfolded protein deposits -including Aβ, tau, and alpha-synuclein. Computational approaches for inhibitor designing, interaction analysis, principal descriptors and an absorption, distribution, metabolism, excretion and toxicity (ADMET) study could speed up the process of drug development with higher efficacy and less chance of failure. This paper reviews the known drugs, drug targets, and existing and future therapies for the treatment of AD.

Monoaminergic neuropathology in Alzheimer’s disease

“…Air pollution exposure especially damages the BBB in the brainstem and can trigger an autoimmune response contributing to the neuroinflammatory and AD pathology present in children from very large urban centers (Calderón-Garcidueñas et al, 2015; Brockmeyer and D’Angiulli, 2016). Even though numerous studies connect specific metals and metalloids with Aβ and tau pathology (e.g., Aβ spontaneously self-aggregates in the presence of divalent metals like Fe, Cu, and Zn into amyloid fibrils, Mandel et al, 2007), recently bringing a “metal hypothesis of AD” into focus (Bush and Tanzi, 2008; Bush, 2013; Singh et al, 2014), such data remain rather controversial, warranting further investigations until convincing conclusions might be drawn. Some environmental toxins, such as β-methylamino- l -alanine (BMAA) produced by cyanobacteria cause misfolding and aggregation of various proteins (Dunlop et al, 2013).…”

Design and Development of Cholinesterase Dual Inhibitors towards Alzheimer's Disease Treatment: A Focus on Recent Contributions from Computational and Theoretical Perspective

“…Different approaches involving 2D-QSAR, 3D-QSAR, docking and statistics methods, were discussed as protocols that could provide essential information on the structural requirement for ligand binding to AChE. [71] A summary on molecular drug targets and therapies for Alzheimer's disease appeared in 2014, the authors [72] documented all the possible targets with known inhibitors for AD treatment. They [72] reiterated that computational approaches are rapidly applicable in drug design and development with appreciable efficiency.…”

The Discovery of Potential Acetyl Cholinesterase Inhibitors: A Combination of Virtual Screening and Molecular Docking Studies

“…The major neuronal death and synaptic loss which is observed in the brain regions responsible for cognitive fuctions of AD is histopathologically characterized , includes the entorhinal cortex, ventral striatum, the cerebral cortex and hippocampus (Gupta et al, 2010). There are two hypothesis which have been proposed for pathophysiology and etiology studies of Alzheimer disease: the first hypothesis refers to the neurodegeneration of amyloid cascade whereas the second hypothesis refers to the malfunction of the cholinergic system which contains metal-mediated toxicity, tau aggregation and inflammation ( According to the neurodegeneration of amyloid cascade hypothesis, Alzheimer disease attars to begin with the proteolytic cleavage of the amyloid precursor protein (APP) and it also results in the production, aggregation, and the deposition of amyloid plaques and β-amyloid (Aβ) (Singh et al, 2014, Cummings et al, 2016.…”

“…The γ-secretase enzyme may be a potentially attractive drug target because it has an important role in the production of Aβ fragments by creating peptides of various lengths, namely Aβ40 and Aβ42 (Singh et al, 2014). It comprises of a molecular complex which has four integral membrane proteins namely:nicastrin, presenilin (PSEN), PEN-2 and APH-1 (Singh et al, 2014, Ahmad and J, 2013).It has been observed that NSAID analogues preferentially inhibit Aβ formation and it does not affect the Notch processing and other developments; so these NSAID analogues may be serve as a lead for optimizing the biological activity or starting point for future drug development against AD (Singh et al,2014).…”

“…AD is a clinical diagnosis; however, the diagnosis of Alzheimer's disease is depend on the depressiondiagnosis, which occurs in approximately 30%-50% of patients with AD (Lu et al, 2012). Motivational disturbancesare more often features in patients committed with ADis depression, such aspsychomotor slowing, fatigue, and apathy, whereas depression in geriatric patients without cognitive impairment tends to feature mood symptoms, such as, suicidality, depressed mood, anxiety, and disturbances in sleep and appetite (Singh et al,2014, Muthusamy et al, 2016. Instruments which are commonly used for assessing depression were designed for use in other patient populations and may be less reliable in patients with AD.…”