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Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate

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  • Yang He

    (Zhejiang University School of Medicine)

  • Mengdi Wei

    (Zhejiang University School of Medicine)

  • Yan Wu

    (Zhejiang University School of Medicine)

  • Huaping Qin

    (Zhejiang University School of Medicine)

  • Weinan Li

    (Zhejiang University School of Medicine)

  • Xiaolin Ma

    (Zhejiang University School of Medicine)

  • Jingjing Cheng

    (Zhejiang University School of Medicine)

  • Jinshuai Ren

    (Zhejiang University School of Medicine)

  • Ye Shen

    (Zhejiang University School of Medicine)

  • Zhong Chen

    (Zhejiang University)

  • Binggui Sun

    (Zhejiang University School of Medicine)

  • Fu-De Huang

    (Chinese Academy of Sciences)

  • Yi Shen

    (Zhejiang University School of Medicine)

  • Yu-Dong Zhou

    (Zhejiang University School of Medicine)

Abstract

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aβ-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aβ induces early synaptic deficits in AD.

Suggested Citation

  • Yang He & Mengdi Wei & Yan Wu & Huaping Qin & Weinan Li & Xiaolin Ma & Jingjing Cheng & Jinshuai Ren & Ye Shen & Zhong Chen & Binggui Sun & Fu-De Huang & Yi Shen & Yu-Dong Zhou, 2019. "Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09114-z
    DOI: 10.1038/s41467-019-09114-z
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