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

Abstract

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

Abstract

Dysregulation of intracellular calcium is reported in Alzheimer’s disease. Here the authors show that loss of the mitochondrial Na ⁺ /Ca ^{2 +} exchanger, NCLX – primary route of mitochondrial calcium efflux, precedes neuronal pathology in experimental models and contributes to Alzheimer’s disease progression.