Amyloid β precursor protein as a molecular target for amyloid β-induced neuronal degeneration in Alzheimer's disease

A role of amyloid beta (A beta) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated A beta have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated A beta remain elusive. In the last 2 decades, a variety of aggregated A beta species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific A beta assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated A beta posit a mayor challenge for the identification of the most cardinal A beta effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid beta precursor protein (APP) as a molecular target for toxic A beta assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking A beta aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD. (C) 2013 Elsevier Inc. All rights reserved.