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

Jadiya, P and Kolmetzky, D W and Tomar, D and Di Meco, A and Lombardi, A A and Lambert, J P and Luongo, T S and Ludtmann, M H R and Praticò, D and Elrod, J W (2019) Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nature Communications, 10 (3885).

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Abstract

Impairments in neuronal intracellular calcium (iCa2+) handling may contribute to Alzheimer’s disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (mCa2+) signaling is a key regulator of both of these processes. Here, we report remodeling of the mCa2+ exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired mCa2+ 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 mCa2+ 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 mCa2+ exchange as potential therapeutic target in AD.