Genetic ablation of neuronal mitochondrial calcium uptake impedes disease progression in models of Alzheimer's disease

ABSTRACT: Loss of mitochondrial Ca2+ (mCa2+) efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mCa2+ overload. Here, we utilize loss-of-function genetic mouse models to causally evaluate the role of mCa2+ uptake by conditionally deleting the mitochondrial calcium uniporter (MCU) in a robust mouse model of AD. Loss of neuronal mCa2+ uptake reduces amyloid-β and tau pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduces matrix Ca2+ content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescues the AD-dependent decline in autophagic capacity and protects neurons against amyloidosis and cell death. This is corroborated by i

SUBMITTER: Pooja Jadiya 

PROVIDER: S-SCDT-10_1038-S44318-026-00809-W | biostudies-other |

REPOSITORIES: biostudies-other