Neuronal Loss of NCLX-Dependent Mitochondrial Calcium Efflux Contributes to Age-Associated Cognitive Decline

Abstract

Mitochondrial and metabolic impairments contribute to neurodegenerative disease development. We recently reported that mitochondrial calcium (mCa2+) overload due to remodeling of the mitochondrial calcium exchange machinery is a causal determinant of cognitive decline in Alzheimer’s disease models. However, whether disrupted mCa2+ signaling contributes to neuronal pathology and cognitive decline independent of precedent amyloidosis or tau pathology remains unknown. Here, we generated mice with neuronal-specific deletion of the mitochondrial sodium/calcium exchanger (NCLX), the primary mechanism of mCa2+ efflux, 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 hyperphosphorylation, and synaptic remodeling. These results demonstrate that loss of NCLX-dependent mCa2+ efflux alone is sufficient to induce an Alzheimer’s disease-like pathology and highlights the promise of therapies targeting mCa2+ exchange.