ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

Bo Jeng Wang; Guor Mour Her; Ming Kuan Hu; Yun Wen Chen; Ying Tsen Tung; Pei Yi Wu; Wen Ming Hsu; Hsinyu Lee; Lee Way Jin; Sheng Ping L. Hwang; Rita P.Y. Chen; Chang Jen Huang; Yung Feng Liao

doi:10.1073/pnas.1618804114

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

Bo Jeng Wang, Guor Mour Her, Ming Kuan Hu, Yun Wen Chen, Ying Tsen Tung, Pei Yi Wu, Wen Ming Hsu, Hsinyu Lee, Lee Way Jin, Sheng Ping L. Hwang, Rita P.Y. Chen, Chang Jen Huang, Yung Feng Liao

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

Original language	English
Pages (from-to)	E3129-E3138
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	15
DOIs	https://doi.org/10.1073/pnas.1618804114
State	Published - 11 Apr 2017

Keywords

Alzheimer’s disease
Autophagy
Aβ
C99
ErbB2

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10.1073/pnas.1618804114

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Wang, B. J., Her, G. M., Hu, M. K., Chen, Y. W., Tung, Y. T., Wu, P. Y., Hsu, W. M., Lee, H., Jin, L. W., Hwang, S. P. L., Chen, R. P. Y., Huang, C. J., & Liao, Y. F. (2017). ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 114(15), E3129-E3138. https://doi.org/10.1073/pnas.1618804114

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title = "ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer{\textquoteright}s disease",

abstract = "Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer{\textquoteright}s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.",

keywords = "Alzheimer{\textquoteright}s disease, Autophagy, Aβ, C99, ErbB2",

author = "Wang, {Bo Jeng} and Her, {Guor Mour} and Hu, {Ming Kuan} and Chen, {Yun Wen} and Tung, {Ying Tsen} and Wu, {Pei Yi} and Hsu, {Wen Ming} and Hsinyu Lee and Jin, {Lee Way} and Hwang, {Sheng Ping L.} and Chen, {Rita P.Y.} and Huang, {Chang Jen} and Liao, {Yung Feng}",

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Wang, BJ, Her, GM, Hu, MK, Chen, YW, Tung, YT, Wu, PY, Hsu, WM, Lee, H, Jin, LW, Hwang, SPL, Chen, RPY, Huang, CJ & Liao, YF 2017, 'ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 15, pp. E3129-E3138. https://doi.org/10.1073/pnas.1618804114

TY - JOUR

T1 - ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

AU - Wang, Bo Jeng

AU - Her, Guor Mour

AU - Hu, Ming Kuan

AU - Chen, Yun Wen

AU - Tung, Ying Tsen

AU - Wu, Pei Yi

AU - Hsu, Wen Ming

AU - Lee, Hsinyu

AU - Jin, Lee Way

AU - Hwang, Sheng Ping L.

AU - Chen, Rita P.Y.

AU - Huang, Chang Jen

AU - Liao, Yung Feng

PY - 2017/4/11

Y1 - 2017/4/11

N2 - Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

AB - Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

KW - Alzheimer’s disease

KW - Autophagy

KW - Aβ

KW - C99

KW - ErbB2

UR - http://www.scopus.com/inward/record.url?scp=85035053134&partnerID=8YFLogxK

U2 - 10.1073/pnas.1618804114

DO - 10.1073/pnas.1618804114

M3 - 期刊論文

C2 - 28351972

AN - SCOPUS:85035053134

SN - 0027-8424

VL - 114

SP - E3129-E3138

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 15

ER -

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

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Keywords

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