Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites.
Synapse loss in cerebral cortex and hippocampus is a prominent feature of Alzheimer's disease (AD) that is correlated with cognitive impairment. Postsynaptic regions of dendrites are subjected to particularly high levels of calcium influx and oxidative stress as a result of local activation of glutamate receptors, and are therefore likely to be sites at which neurodegenerative processes are initiated in AD. Data suggest that neurons may die in AD by a process called apoptosis which involves a stereotyped series of biochemical changes that culminate in nuclear fragmentation, and that amyloid beta-peptide (Abeta) may play a role in such apoptosis. We now report that Abeta induces apoptosis-related biochemical changes in cortical synaptosomes, and in dendrites of cultured hippocampal neurons. Exposure of synaptosomes to Abeta resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial membrane depolarization. Cytosolic extracts from synaptosomes exposed to Abeta induced chromatin condensation and fragmentation in isolated nuclei indicating that signals capable of inducing nuclear apoptosis can be generated locally in synapses. Exposure of cultured hippocampal neurons to Abeta resulted in caspase activation and mitochondrial membrane depolarization in dendrites and cell bodies. A caspase inhibitor prevented Abeta-induced mitochondrial membrane depolarization in synaptosomes, and mitochondrial membrane depolarization and nuclear apoptosis in cultured hippocampal neurons. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated in synapses and dendrites by Abeta, and suggest that such 'synaptic apoptosis' may contribute to synaptic dysfunction and degeneration in AD.
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, 211 Sanders-Brown Building, University of Kentucky, Lexington, KY 40536, USA. mmattson@aging.coa.uky.edu
M P
MP
Mattson
J
J
Partin
J G
JG
Begley
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002474:Cell-Free System / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D003712:Dendrites / Q000187:drug effects*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects
D016229:Amyloid beta-Peptides