title: TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production.
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.
authors.affiliation: 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, 320 Yue-Yang Road, Shanghai 200031, China.|Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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, 320 Yue-Yang Road, Shanghai 200031, China.|Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Physiology and Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, and Beijing Institute for Brain Disorders, 10 Xitoutiao, You'anmen Wai, Beijing 100069, China.|Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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, 320 Yue-Yang Road, Shanghai 200031, China.|Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: 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, 320 Yue-Yang Road, Shanghai 200031, China.|Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhuohao
authors.initials: Z
authors.lastname: He
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, SIBS, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Naihe
authors.initials: N
authors.lastname: Jing
authors.affiliation: Department of Physiology and Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, and Beijing Institute for Brain Disorders, 10 Xitoutiao, You'anmen Wai, Beijing 100069, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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, 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D053829:Amyloid Precursor Protein Secretases