TRPC6 Specifically Interacts with APP to Inhibit Its Cleavage by γ-secretase and Reduce Aβ Production

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Nov 20

PMID 26581893

Citations 37

Authors

Junfeng Wang

Rui Lu

Jian Yang

Hongyu Li

Zhuohao He

Naihe Jing

Xiaomin Wang

Yizheng Wang

Affiliations

Soon will be listed here.

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.

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References

Verghese P, Castellano J, Garai K, Wang Y, Jiang H, Shah A . ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013; 110(19):E1807-16. PMC: 3651443. DOI: 10.1073/pnas.1220484110. View

Xia W, Wolfe M . Intramembrane proteolysis by presenilin and presenilin-like proteases. J Cell Sci. 2003; 116(Pt 14):2839-44. DOI: 10.1242/jcs.00651. View

Griesi-Oliveira K, Acab A, Gupta A, Sunaga D, Chailangkarn T, Nicol X . Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry. 2014; 20(11):1350-65. PMC: 4427554. DOI: 10.1038/mp.2014.141. View

Phiel C, Wilson C, Lee V, Klein P . GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003; 423(6938):435-9. DOI: 10.1038/nature01640. View

Jankowsky J, Slunt H, Ratovitski T, Jenkins N, Copeland N, Borchelt D . Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001; 17(6):157-65. DOI: 10.1016/s1389-0344(01)00067-3. View

Montell C, Birnbaumer L, Flockerzi V . The TRP channels, a remarkably functional family. Cell. 2002; 108(5):595-8. DOI: 10.1016/s0092-8674(02)00670-0. View

Lee M, Kao S, Lemere C, Xia W, Tseng H, Zhou Y . APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol. 2003; 163(1):83-95. PMC: 2173445. DOI: 10.1083/jcb.200301115. View

Clapham D . TRP channels as cellular sensors. Nature. 2003; 426(6966):517-24. DOI: 10.1038/nature02196. View

Tanzi R, Moir R, Wagner S . Clearance of Alzheimer's Abeta peptide: the many roads to perdition. Neuron. 2004; 43(5):605-8. DOI: 10.1016/j.neuron.2004.08.024. View

10.

Merritt J, Armstrong W, Benham C, Hallam T, Jacob R, Leigh B . SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem J. 1990; 271(2):515-22. PMC: 1149585. DOI: 10.1042/bj2710515. View

11.

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

12.

Gomez-Isla T, Price J, McKeel Jr D, Morris J, Growdon J, Hyman B . Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci. 1996; 16(14):4491-500. PMC: 6578866. View

13.

Schroeter E, Kisslinger J, Kopan R . Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998; 393(6683):382-6. DOI: 10.1038/30756. View

14.

Hofmann T, Obukhov A, Schaefer M, Harteneck C, Gudermann T, Schultz G . Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999; 397(6716):259-63. DOI: 10.1038/16711. View

15.

Lessard C, Lussier M, Cayouette S, Bourque G, Boulay G . The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal. 2004; 17(4):437-45. DOI: 10.1016/j.cellsig.2004.09.005. View

16.

Gomez-Ospina N, Tsuruta F, Barreto-Chang O, Hu L, Dolmetsch R . The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell. 2006; 127(3):591-606. PMC: 1750862. DOI: 10.1016/j.cell.2006.10.017. View

17.

Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T . TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 2006; 440(7088):1208-12. DOI: 10.1038/nature04667. View

18.

Kim J, Choi S, Jung J, Roh E, Kim H . Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPalpha) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH-SY5Y cells. J Neurochem. 2006; 97(1):245-54. DOI: 10.1111/j.1471-4159.2006.03734.x. View

19.

Flajolet M, He G, Heiman M, Lin A, Nairn A, Greengard P . Regulation of Alzheimer's disease amyloid-beta formation by casein kinase I. Proc Natl Acad Sci U S A. 2007; 104(10):4159-64. PMC: 1820725. DOI: 10.1073/pnas.0611236104. View

20.

Jia Y, Zhou J, Tai Y, Wang Y . TRPC channels promote cerebellar granule neuron survival. Nat Neurosci. 2007; 10(5):559-67. DOI: 10.1038/nn1870. View