Abstract
Alzheimer’s disease (AD) is characterized by the extracellular deposition of amyloid beta, intracellular neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. These phenotypes correlate with and are linked to elevated neuronal intracellular calcium (iCa2+) levels. Recently, our group reported that mitochondrial calcium (mCa2+) overload, due to loss of mCa2+ efflux capacity, contributes to AD development and progression. We also noted proteomic remodeling of the mitochondrial calcium uniporter channel (mtCU) in sporadic AD brain samples, suggestive of altered mCa2+ uptake in AD. Since the mtCU is the primary mechanism for Ca2+ uptake into the mitochondrial matrix, inhibition of the mtCU has the potential to reduce or prevent mCa2+ overload in AD. Here, we report that neuronal-specific loss of mtCU-dependent mCa2+ uptake in the 3xTg-AD mouse model of AD reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline. Knockdown of Mcu in a cellular model of AD significantly decreased matrix Ca2+ content, oxidative stress and cell death. These results suggest that inhibition of neuronal mCa2+ uptake is a novel therapeutic target to impede AD progression.
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