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

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

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

Lugar: New York; Año: 2013 vol. 34 p. 2525 - 2537

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.