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APP intracellular domain-WAVE1 pathway reduces amyloid-beta production

Title
APP intracellular domain-WAVE1 pathway reduces amyloid-beta production
Authors
Ceglia, IlariaReitz-, ChristianeGresack, JodiAhn, Jung-HyuckBustos, VictorBleck, MarinaZhang, XiaozhuMartin, GrantSimon, Sanford M.Nairn, Angus C.Greengard, PaulKim, Yong
Ewha Authors
안정혁
SCOPUS Author ID
안정혁scopus
Issue Date
2015
Journal Title
NATURE MEDICINE
ISSN
1078-8956JCR Link1546-170XJCR Link
Citation
vol. 21, no. 9, pp. 1054 - +
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
An increase in amyloid-beta (A beta) 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 A beta 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 A beta. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced A beta 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 Ab production.
DOI
10.1038/nm.3924
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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