Neuronal loss of NCLX-dependent mitochondrial calcium efflux mediates age-associated cognitive decline

Mitochondrial calcium overload contributes to neurodegenerative disease development and progression. We recently reported that loss of the mitochondrial sodium/calcium exchanger (NCLX), the primary mechanism of (m)Ca(2+) efflux, promotes (m)Ca(2+) overload, metabolic derangement, redox stress, and cognitive decline in models of Alzheimer’s disease (AD). However, whether disrupted (m)Ca(2+) signaling contributes to neuronal pathology and cognitive decline independent of pre-existing amyloid or tau pathology remains unknown. Here, we generated mice with neuronal deletion of the mitochondrial sodium/calcium exchanger (NCLX, Slc8b1 gene), and evaluated age-associated changes in cognitive function and neuropathology. Neuronal loss of NCLX resulted in an age-dependent decline in spatial and cued recall memory, moderate amyloid deposition, mild tau pathology, synaptic remodeling, and indications of cell death. These results demonstrate that loss of NCLX-dependent (m)Ca(2+) efflux alone is sufficient to induce an Alzheimer’s disease-like pathology and highlights the promise of therapies targeting (m)Ca(2+) exchange.