Genetic ablation of neuronal mitochondrial calcium uptake halts Alzheimer's disease progression

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 ( _i Ca ²⁺ ) levels. Recently, our group reported that mitochondrial calcium ( _m Ca ²⁺ ) overload, due to loss of _m Ca ²⁺ 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 _m Ca ²⁺ uptake in AD. Since the mtCU is the primary mechanism for Ca ²⁺ uptake into the mitochondrial matrix, inhibition of the mtCU has the potential to reduce or prevent _m Ca ²⁺ overload in AD. Here, we report that neuronal-specific loss of mtCU-dependent _m Ca ²⁺ 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 Ca ²⁺ content, oxidative stress, and cell death. These results suggest that inhibition of neuronal _m Ca ²⁺ uptake is a novel therapeutic target to impede AD progression.