Potential Neuroprotective Peptide Emerged from Dual Neurotherapeutic Targets: A Fusion Approach for the Development of anti-Alzheimer's Lead.

Amyloid-beta (Aβ) peptide misfolds into fibrillary aggregates (β-sheet) and deposited as amyloid plaques in the cellular environment, which severely damages intraneuronal connections leading to Alzheimer's disease (AD) pathogenesis. Furthermore, neurons are rich in tubulin/microtubule and the intracellular network of microtubules also gets disrupted by the accumulation of Aβ fiber in brain. Hence, development of new potent molecules, which can simultaneously inhibit Aβ fibrillations and stabilize microtubules, is particularly needed for the efficient therapeutic application in AD. To address these issues, here we introduced an innovative fusion strategy to design and develop next generation anti-AD therapeutic leads. This unexplored fusion strategy entails design and development of a potent nonapeptide by taking into account both the hydrophobic core (17-21) of Aβ peptide and the taxol binding region of β-tubulin. In vitro results suggest that this newly designed peptide interacts at the taxol binding region of β-tubulin with a moderate binding affinity and promotes microtubule polymerization. It has the ability to bind at the hydrophobic core (17-21) of Aβ, responsible for its aggregation and prevent the amyloid fibril as well as plaques formation. In addition, it interacts at the CAS site (catalytic anionic site) of acetylcholinesterase (AChE) and significantly inhibits AChE induced Aβ fibrillation, stimulates neurite branching, provides stability to intracellular microtubules and extensive protection of neurons against nerve growth factor (NGF) deprived neuron toxicity. Moreover, this newly designed peptide shows good stability in serum obtained from humans and efficiently permeates the blood-brain barrier (BBB) without showing any toxicity towards differentiated PC12 neurons as well as primary rat cortical neurons. This excellent feature of protecting the neurons by stabilizing the microtubules without showing any toxicity towards neurons will make this peptide a potent therapeutic agent of AD in near future.