Many cases of early-onset inherited
Alzheimer's disease (AD) are caused by mutations in the
presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular
calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that
cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after
stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of
brain injury after focal
cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to
glucose deprivation and chemical
hypoxia compared to their wild-type counterparts.
Calcium imaging studies demonstrated enhanced elevation of intracellular
calcium levels after
glucose deprivation and chemical
hypoxia in neurons from PS1 mutant mice. Agents that block
calcium release from IP(3)- and
ryanodine-sensitive stores (xestospongin and
dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that
presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related
ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum
calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.