Amyloid b precursor protein as a molecular target for amyloid beinduced neuronal degeneration in Alzheimer’s disease

ELENA ANAHI BIGNANTE; FLORENCIA HEREDIA; GERARDO MORFINI; ALFREDO LORENZO

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2013

0197-4580

A role of amyloid b (Ab) peptide aggregation and deposition in Alzheimer’s disease (AD) pathogenesis iswidely accepted. Significantly, abnormalities induced by aggregated Ab have been linked to synaptic andneuritic degeneration, consistent with the “dying-back” pattern of degeneration that characterizesneurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Abremain elusive. In the last 2 decades, a variety of aggregated Ab species have been identified and theirtoxic properties demonstrated in diverse experimental systems. Concurrently, specific Ab assemblieshave been shown to interact and misregulate a growing number of molecular effectors with diversephysiological functions. Such pleiotropic effects of aggregated Ab posit a mayor challenge for the identificationof the most cardinal Ab effectors relevant to AD pathology. In this review, we discuss recentexperimental evidence implicating amyloid b precursor protein (APP) as a molecular target for toxic Abassemblies. Based on a significant body of pathologic observations and experimental evidence, wepropose a novel pathologic feed-forward mechanism linking Ab aggregation to abnormalities in APPprocessing and function, which in turn would trigger the progressive loss of neuronal connectivityobserved early in AD.