An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD)1,2, but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.
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This work was supported by the US National Institutes of Health (grants AG009464 (to P.G.) and AG047270 (to A.C.N.)), the Fisher Center for Alzheimer's Research Foundation (to P.G.) and the US Department of Defense–USAMRAA (grants W81XWH-09-1-0392 (to Y.K.) and W81XWH-09-1-0402 (to P.G.)). J.-H.A. was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2010-0027945). We thank W. Luo for protocols for metabolic pulse labeling and chase and organelle fractionation; W.J. Netzer (The Rockefeller University, New York, New York, USA) for sAPPβ antibody and mNotchΔE plasmid; D. Cai for the budding-assay protocol; and S.S. Sisodia for the pCB6-APP695wt and pCB6-APP695swe plasmids. We also thank A. Schaeffer, P. Kurup, P. Lombroso, D. Tampellini, G. Gouras and R. Moir for discussion or sharing of materials. We acknowledge R. Norinsky and The Rockefeller University Transgenics Services Laboratory for their excellent in vitro fertilization services, Z. Dong for research assistance and E. Griggs for graphics.
The authors declare no competing financial interests.
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Ceglia, I., Reitz, C., Gresack, J. et al. APP intracellular domain–WAVE1 pathway reduces amyloid-β production. Nat Med 21, 1054–1059 (2015) doi:10.1038/nm.3924
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