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TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production

Author

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  • Junfeng Wang

    (Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, SIBS, CAS
    Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Rui Lu

    (Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, SIBS, CAS
    Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Jian Yang

    (Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, and Beijing Institute for Brain Disorders
    Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University)

  • Hongyu Li

    (Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, SIBS, CAS
    Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Zhuohao He

    (Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, SIBS, CAS
    Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Naihe Jing

    (State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, SIBS, Chinese Academy of Sciences)

  • Xiaomin Wang

    (Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, and Beijing Institute for Brain Disorders)

  • Yizheng Wang

    (Laboratory of Neural Signal Transduction, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, SIBS, CAS)

Abstract

Generation of β-amyloid (Aβ) peptide in Alzheimer’s disease involves cleavage of amyloid precursor protein (APP) by γ-secretase, a protease known to cleave several substrates, including Notch. Finding specific modulators for γ-secretase could be a potential avenue to treat the disease. Here, we report that transient receptor potential canonical (TRPC) 6 specifically interacts with APP leading to inhibition of its cleavage by γ-secretase and reduction in Aβ production. TRPC6 interacts with APP (C99), but not with Notch, and prevents C99 interaction with presenilin 1 (PS1). A fusion peptide derived from TRPC6 also reduces Aβ levels without effect on Notch cleavage. Crossing APP/PS1 mice with TRPC6 transgenic mice leads to a marked reduction in both plaque load and Aβ levels, and improvement in structural and behavioural impairment. Thus, TRPC6 specifically modulates γ-secretase cleavage of APP and preventing APP (C99) interaction with PS1 via TRPC6 could be a novel strategy to reduce Aβ formation.

Suggested Citation

  • Junfeng Wang & Rui Lu & Jian Yang & Hongyu Li & Zhuohao He & Naihe Jing & Xiaomin Wang & Yizheng Wang, 2015. "TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9876
    DOI: 10.1038/ncomms9876
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