Abstract
Loss of (m) Ca (2+) efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mitochondrial Ca (2+) ( (m) Ca (2+) ) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of (m) Ca (2+) uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal (m) Ca (2+) uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca (2+) content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu . These results suggest that inhibition of neuronal (m) Ca (2+) uptake represents a powerful therapeutic target to impede AD progression.