Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11813-6
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Funding
- NIH [R01HL136954, R01HL123966, 3R01HL123966-05S1, R01HL142271]
- Pennsylvania Dept. of Health CURE Award [420792]
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Impairments in neuronal intracellular calcium (Ca-i(2+)) handling may contribute to Alzheimer's disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (Ca-m(2+)) signaling is a key regulator of both of these processes. Here, we report remodeling of the Ca-m(2+) exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired Ca-m(2+) efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na+/Ca2+ exchanger (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that Ca-m(2+) overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest Ca-m(2+) exchange as potential therapeutic target in AD.
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