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

Junfeng Wang,R. Lu,Jian Yang,Hongyu Li,Zhuohao He,N. Jing,Xiaomin Wang,Yizheng Wang

Published 2015 in Nature Communications

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. Attempts to treat Alzheimer's disease by targeting γ-secretase cleavage of APP into Aß have been unsuccessful, partially due to off-target effects. Here, the authors identify TRPC6 as a novel γ-secretase modulator, showing that it interacts with APP to regulate Aß levels while sparing Notch cleavage.

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