Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease

Impairments in neuronal intracellular calcium ((i)Ca(2+)) handling may contribute to Alzheimer’s disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium ((m)Ca(2+)) signaling is a key regulator of both of these processes. Here, we report remodeling of the (m)Ca(2+) exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired (m)Ca(2+) efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na(+)/Ca(2+) 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 (m)Ca(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 (m)Ca(2+) exchange as potential therapeutic target in AD.