Apoptosis is secondary to non-apoptotic axonal degeneration in neurons exposed to Aβ in distal axons

The goal of this study was to assess if neurons exposed to amyloid-beta peptide (A beta) 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 A beta(1-42) activates an independent destruction program in axons, which leads to nuclear apoptosis. A beta-induced axonal degeneration does not involve local caspase activation, but causes caspase activation in cell bodies. Accordingly, inhibition of caspase activation blocks A beta-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 A beta-induced apoptosis. However, our data indicate that A beta-induced axonal degeneration follows a mechanism different than that activated by NGF withdrawal. Only A beta-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 A beta-induced axonal degeneration by calpastatin prevents nuclear apoptosis. (c) 2005 Published by Elsevier Inc.