Mitochondrial calcium uniporter knockdown in hippocampal neurons effectively attenuates synaptic plasticity impairment and pathology in APP/PS1/tau model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa2+) uptake, and its dysregulation contributes to calcium imbalance and mitochondrial impairment. In this study, we investigated the effects of MCU knockdown in hippocampal neurons on synaptic plasticity and neuropathology in APP/PS1/tau mice. It was found that MCU knockdown reduced mCa2+ overload, restored mitochondrial membrane potential (MMP), and attenuated excessive reactive oxygen species (ROS) production in the hippocampus. These mitochondrial improvements were associated with a rescue of impaired synaptic plasticity, including enhanced long-term potentiation (LTP) and reduced long-term depression (LTD) through activating the CaMKII/CREB/BDNF/TrkB signaling pathway. Furthermore, MCU knockdown alleviated hippocampal amyloid β (Aβ) pathology by decreasing APP/BACE1/RAGE levels while increasing NEP/LRP1 levels, and mitigated tau pathology through downregulation of GSK3β/CDK5 expression. In addition, hippocampal neuronal number and activity were improved, as reflected by increased N-acetylaspartic acid (NAA)/creatine (Cr) and glutamic acid (Glu)/Cr. Collectively, these findings indicated that MCU knockdown in hippocampal neurons ameliorated mitochondrial dysfunction, synaptic deficits, and AD-related pathology, highlighting MCU as a potential therapeutic target for AD.