Abstract
Alzheimer's disease is characterized by amyloid β-peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin-1 gene on chromosome 14 are causally linked to many cases of early-onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin-1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid β-peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild-type presenilin-1. Mitochondrial dysfunction and caspase activation following exposures to amyloid β-peptide and metabolic insults were exacerbated in synaptosomes from presenilin-1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin-1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin-1 mutations.
Original language | English (US) |
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Pages (from-to) | 1030-1039 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 72 |
Issue number | 3 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Alzheimer's disease
- Amyloid
- Apoptosis
- Caspase
- Depolarization
- Reactive oxygen species
- Synaptosomes
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience