Abstract:
Alzheimer’s Disease (AD) is a polygenic progressive neurological disorder which
effect about 45 million people worldwide. It is characterized by the deposition of
amyloid beta (A) plaques and neurofibrillary tangles (NFTs) in the brain. The FDA
approved drugs for AD temporarily slower the progression of the disease however there
are no therapeutic drugs that permanently inhibit progression or reverse the neural
degradation in AD. Emerging evidence indicated molecular association between
diabetes mellitus type 2 (T2DM) and AD that led to examine the effects of several anti diabetic medications against AD. In this study, we performed a comparative assessment
of therapeutic effects of Metformin, a widely prescribed anti diabetic drug and
Donepezil, a classical drug for AD that inhibit cholinesterase and in turn up-regulate
acetylcholine thus enhancing cholinergic transmission. The aluminium chloride
(AlCl3)-induced neurotoxicity mouse models were used to study AD associated
aberrations and were placed into two groups treated with Donepezil and Metformin
(n=8, each group), while the control group was administered distilled water only. A 2-
Dimensional Gel electrophoresis and SDS-PAGE analysis was performed to evaluate
the differentially expressed proteins in the treated groups. AlCl3 induced the formation
of A plaques in hippocampus, whereas significant differences were observed in
Donepezil and Metformin-treated groups evident through histological assessment of the
treated tissue sections. Interestingly, Metformin-treatment reduced the A plaques
formation and normalized the protein expression pattern. Moreover, molecular docking
analysis was also performed to compare the binding potential of Donepezil and
Metformin with pathologically significant proteins involved in AD associated
molecular dysregulation. Interestingly, Metformin showed strong binding affinity with
xii
the target proteins. Doublecortin (DCX), Presinilin (PSEN1), and Ki-67 showed the
most stable conformations in comparison to Donepezil. In conclusion, these findings
reemphasize proteomic alterations in AD and suggested a potential effect of antidiabetic
drug on aberrant protein expression which provides basis for future drug repurposing
for better therapeutic interventions for AD
