Abstract
Given the present challenges to attain effective treatment for β-amyloid (Aβ) toxicity in neurodegenerative disorders such as Alzheimer’s disease, development of novel cytoprotective pathways that can assist immune mediated therapies through the preservation of central nervous system microglia could offer significant promise. We show that the CCN4 protein, Wnt1 inducible signaling pathway protein 1 (WISP1), is initially up-regulated by Aβ and can modulate its endogenous expression for the protection of microglia during Aβ mediated apoptosis. WISP1 activates mTOR and phosphorylates p70S6K and 4EBP1 through the control of the regulatory mTOR component PRAS40. Loss of PRAS40 through gene reduction or inhibition by WISP1 is cytoprotective. WISP1 ultimately governs PRAS40 by sequestering PRAS40 intracellularly through post-translational phosphorylation and binding to protein 14-3-3. Our work identifies WISP1, mTOR signaling, and PRAS40 as targets for new strategies directed against Alzheimer’s disease and related disorders.
Keywords: Alzheimer’s disease, amyloid, CCN4, microglia, mTOR, PRAS40, WISP1, novel cytoprotective pathways, renal fibroblasts, phosphatidylinositol-3-kinase
Current Neurovascular Research
Title:Wnt1 Inducible Signaling Pathway Protein 1 (WISP1) Targets PRAS40 to Govern β-Amyloid Apoptotic Injury of Microglia
Volume: 9 Issue: 4
Author(s): Yan Chen Shang, Zhao Zhong Chong, Shaohui Wang and Kenneth Maiese
Affiliation:
Keywords: Alzheimer’s disease, amyloid, CCN4, microglia, mTOR, PRAS40, WISP1, novel cytoprotective pathways, renal fibroblasts, phosphatidylinositol-3-kinase
Abstract: Given the present challenges to attain effective treatment for β-amyloid (Aβ) toxicity in neurodegenerative disorders such as Alzheimer’s disease, development of novel cytoprotective pathways that can assist immune mediated therapies through the preservation of central nervous system microglia could offer significant promise. We show that the CCN4 protein, Wnt1 inducible signaling pathway protein 1 (WISP1), is initially up-regulated by Aβ and can modulate its endogenous expression for the protection of microglia during Aβ mediated apoptosis. WISP1 activates mTOR and phosphorylates p70S6K and 4EBP1 through the control of the regulatory mTOR component PRAS40. Loss of PRAS40 through gene reduction or inhibition by WISP1 is cytoprotective. WISP1 ultimately governs PRAS40 by sequestering PRAS40 intracellularly through post-translational phosphorylation and binding to protein 14-3-3. Our work identifies WISP1, mTOR signaling, and PRAS40 as targets for new strategies directed against Alzheimer’s disease and related disorders.
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Cite this article as:
Chen Shang Yan, Zhong Chong Zhao, Wang Shaohui and Maiese Kenneth, Wnt1 Inducible Signaling Pathway Protein 1 (WISP1) Targets PRAS40 to Govern β-Amyloid Apoptotic Injury of Microglia, Current Neurovascular Research 2012; 9 (4) . https://dx.doi.org/10.2174/156720212803530618
DOI https://dx.doi.org/10.2174/156720212803530618 |
Print ISSN 1567-2026 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5739 |
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