Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice.
Alzheimer's disease is characterized by amyloid beta-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 beta-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 beta-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.
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
J G
JG
Begley
W
W
Duan
S
S
Chan
K
K
Duff
M P
MP
Mattson
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000648:ultrastructure; D002614:Chelating Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D005838:Genotype; D006706:Homeostasis; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D053764:Presenilin-1; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002614:Chelating Agents; D008565:Membrane Proteins; D053764:Presenilin-1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002118:Calcium