title: Amyloid β precursor protein as a molecular target for amyloid β--induced neuronal degeneration in Alzheimer's disease.
abstract: A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ 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 Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
authors.affiliation: Laboratory of Experimental Neuropathology, Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, 5016 Córdoba, Argentina.
authors.forename: Elena Anahi
authors.initials: EA
authors.lastname: Bignante
authors.forename: Florencia
authors.initials: F
authors.lastname: Heredia
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Lorenzo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D002448:Cell Adhesion; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009410:Nerve Degeneration / Q000209:etiology*; D009473:Neuronal Plasticity
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor
keywords: APP; Alzheimer's disease; Aβ; Dying-back degeneration; Neuritic dystrophy; Synaptic degeneration