Amyloid β-peptide induces apoptosis-related events in synapses and dendrites

Mark P. Mattson, James Partin, J. G. Begley

Research output: Contribution to journalArticlepeer-review

Abstract

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 β-peptide (Aβ) may play a role in such apoptosis. We now report that Aβ induces apoptosis-related biochemical changes in cortical synaptosomes, and in dendrites of cultured hippocampal neurons. Exposure of synaptosomes to Aβ resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial membrane depolarization. Cytosolic extracts from synaptosomes exposed to Aβ 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 Aβ resulted in caspase activation and mitochondrial membrane depolarization in dendrites and cell bodies. A caspase inhibitor prevented Aβ-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 Aβ, and suggest that such 'synaptic apoptosis' may contribute to synaptic dysfunction and degeneration in AD.

Original languageEnglish (US)
Pages (from-to)167-176
Number of pages10
JournalBrain Research
Volume807
Issue number1-2
DOIs
StatePublished - Oct 5 1998
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Caspase
  • Dendritic spine
  • Mitochondrial transmembrane potential
  • Oxidative stress
  • Phosphatidylserine
  • Synaptosome

ASJC Scopus subject areas

  • Neuroscience(all)

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