title: Apoptosis is secondary to non-apoptotic axonal degeneration in neurons exposed to Abeta in distal axons.
abstract: The goal of this study was to assess if neurons exposed to amyloid-beta peptide (Abeta) exclusively in distal axons, undergo apoptosis. This is relevant to the loss of cholinergic neurons in Alzheimer's disease. Using a three-compartmented culture system for rat sympathetic neurons, we demonstrate that exposure of axons to Abeta1-42 activates an independent destruction program in axons, which leads to nuclear apoptosis. Abeta-induced axonal degeneration does not involve local caspase activation, but causes caspase activation in cell bodies. Accordingly, inhibition of caspase activation blocks Abeta-induced apoptosis but not axonal degeneration. In agreement with previous suggestions that disruption of nerve growth factor (NGF)-mediated signaling might contribute to the loss of cholinergic neurons, we found that provision of NGF to cell bodies protects sympathetic neurons from Abeta-induced apoptosis. However, our data indicate that Abeta-induced axonal degeneration follows a mechanism different than that activated by NGF withdrawal. Only Abeta-induced axonal degeneration is prevented by the calpain inhibitor calpastatin and is insensitive to the inhibitor of the ubiquitin-proteasome system MG132. Importantly, inhibition of Abeta-induced axonal degeneration by calpastatin prevents nuclear apoptosis.
authors.affiliation: Centre for Alzheimer and Neurodegenerative Research, Signal Transduction Research Group and Department of Pharmacology, 928 Medical Science Building, Faculty of Medicine, University of Alberta, Edmonton, Alta., Canada T6G 2H7.
authors.forename: Mee-Sook
authors.initials: MS
authors.lastname: Song
authors.forename: Lucila
authors.initials: L
authors.lastname: Saavedra
authors.forename: Elena I Posse
authors.initials: EI
authors.lastname: de Chaves
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000931:Antidotes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity*; D016548:Prosencephalon / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D000931:Antidotes; D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D004533:Egtazic Acid; C033668:calpastatin; D020932:Nerve Growth Factor; D002154:Calpain; C022616:thiazolyl blue