Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice

Excitotoxicity, a form of neuronal injury in which excessive activation of glutamate receptors results in cellular calcium overload(1,2) has been impl icated in the pathogenesis of Alzheimer disease(3,4) (AD), although direct evidence is lacking. Mutations in the presenilin-1 (PS1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD (refs. 5, 6). We generated PS1 mutant mice (PS1M146VKI) that express the PS1 M146V ta rgeted allele at normal physiological levels. Although PS1M146VKI mice have no overt mutant phenotype, they are hypersensitive to seizure-induced syna ptic degeneration and necrotic neuronal death in the hippocampus. Cultured hippocampal neurons from PS1M146VKI mice have increased vulnerability to de ath induced by glutamate, which is correlated with perturbed calcium homeos tasis, increased oxidative stress and mitochondrial dysfunction. Agents tha t suppress calcium influx or release and antioxidants protect neurons again st the excitotoxic action of the PS1 mutation. These findings establish a d irect link between a genetic defect that causes AD and excitotoxic neuronal degeneration, and indicate new avenues for therapeutic intervention in AD patients.