TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production
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...
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Nature Publishing Group
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696454/ |
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pubmed-46964542016-01-12 TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production Wang, Junfeng Lu, Rui Yang, Jian Li, Hongyu He, Zhuohao Jing, Naihe Wang, Xiaomin Wang, Yizheng Article 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. Nature Publishing Group 2015-11-19 /pmc/articles/PMC4696454/ /pubmed/26581893 http://dx.doi.org/10.1038/ncomms9876 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Wang, Junfeng Lu, Rui Yang, Jian Li, Hongyu He, Zhuohao Jing, Naihe Wang, Xiaomin Wang, Yizheng |
| spellingShingle |
Wang, Junfeng Lu, Rui Yang, Jian Li, Hongyu He, Zhuohao Jing, Naihe Wang, Xiaomin Wang, Yizheng TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| author_facet |
Wang, Junfeng Lu, Rui Yang, Jian Li, Hongyu He, Zhuohao Jing, Naihe Wang, Xiaomin Wang, Yizheng |
| author_sort |
Wang, Junfeng |
| title |
TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| title_short |
TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| title_full |
TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| title_fullStr |
TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| title_full_unstemmed |
TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production |
| title_sort |
trpc6 specifically interacts with app to inhibit its cleavage by γ-secretase and reduce aβ production |
| description |
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. |
| publisher |
Nature Publishing Group |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696454/ |
| _version_ |
1613518415796895744 |