Apoptosis is secondary to non-apoptotic axonal degeneration in neurons exposed to Abeta in distal axons.
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.
Song
Mee-Sook
MS
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.
Saavedra
Lucila
L
de Chaves
Elena I Posse
EI
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
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