MCU knockdown in hippocampal neurons improves memory performance of an Alzheimer’s disease mouse model

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Alzheimer’s disease (AD) is a progressive and degenerative disorder accompanied by cognitive decline, but effective strategies against AD are currently not available. Recently, mitochondrial dysfunction has been shown to promote the development of AD. The mitochondrial calcium uniporter (MCU) is a key channel of mitochondrial Ca2+ (mCa2+) uptake. Abnormal expression of MCU can induce an imbalance in mCa2+ homeostasis, ultimately leading to mitochondrial dysfunction. Importantly, we have observed that the expression level of MCU in the hippocampus of APP/PS1/tau transgenic mice is much higher than that of control C57 mice, suggesting that MCU may be a target for developing treatment strategies for AD. In the present study, we reveal for the first time that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through radial arm maze task. Western blot analysis, transmission electron microscopy (TEM), Golgi staining, immunohistochemistry (IHC) and ELISA results demonstrate that MCU knockdown in hippocampal neurons upregulates the levels of postsynaptic density protein 95 (PSD95) and synaptophysin (SYP), and increases the numbers of synapses and dendritic spines. Meanwhile, MCU knockdown in hippocampal neurons decreases the neuroinflammatory response induced by astrogliosis and high levels of IL-1β and TNF-α, and improves the PINK1-Parkin mitophagy signaling pathway and increases the level of Beclin-1 but decreases the level of P62. In addition, MCU knockdown in hippocampal neurons recovers the average volume and number of mitochondria. These data confirm that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through ameliorating the synapse structure and function, relieving the inflammation response and recovering mitophagy, indicating that MCU inhibition has the potential to be developed as a novel therapy for AD.