The Y682ENPTY687 motif of APP: Progress and insights toward a targeted therapy for Alzheimer’s disease patients

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which no curative treatments, disease modifying strategies or effective symptomatic therapies exist. Current pharmacologic treatments for AD can only decelerate the progression of the disease for a short time, often at the cost of severe side effects. Therefore, there is an urgent need for biomarkers able to diagnose AD at its earliest stages, to conclusively track disease progression, and to accelerate the clinical development of innovative therapies.Scientific research and economic efforts for the development of pharmacotherapies have recently homed in on the hypothesis that neurotoxic β-amyloid (Aβ) peptides in their oligomeric or fibrillary forms are primarily responsible for the cognitive impairment and neuronal death seen in AD. As such, modern pharmacologic approaches are largely based on reducing production by inhibiting β and γ secretase cleavage of the amyloid precursor protein (APP) or on dissolving existing cerebral Aβ plaques or to favor Aβ clearance from the brain.The following short review aims to persuade the reader of the idea that APP plays a much larger role in AD pathogenesis. APP plays a greater role in AD pathogenesis than its role as the precursor for Aβ peptides: both the abnormal cleavage of APP leading to Aβ peptide accumulation and the disruption of APP physiological functions contribute to AD pathogenesis.We summarize our recent results on the role played by the C-terminal APP motif -the Y682ENPTY68 motif- in APP function and dysfunction, and we provide insights into targeting the Tyr682 residue of APP as putative novel strategy in AD.