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

Abstract

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive decline, which could be promoted by mitochondrial dysfunction induced by mitochondrial Ca ²⁺ (mCa ²⁺) homeostasis Mitochondrial calcium uniporter (MCU), a key channel of mCa ²⁺ uptake, may be a target for AD treatment. In the present study, we reveal for the first time that <i>MCU</i> 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 <i>MCU</i> 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, <i>MCU</i> 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, <i>MCU</i> knockdown in hippocampal neurons recovers the average volume and number of mitochondria. These data confirm that <i>MCU</i> 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.