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

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 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.

• Publication year

  2022

• Venue

  Acta Biochimica et Biophysica Sinica

• Publication date

  2022-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3724/abbs.2022138PMID 36239352PMCID 9828087
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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