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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, Ilaria; Reitz-, Christiane; Gresack, Jodi; Ahn, Jung-Hyuck; Bustos, Victor; Bleck, Marina; Zhang, Xiaozhu; Martin, Grant; Simon, Sanford M.; Nairn, Angus C.; Greengard, Paul; Kim, Yong
- Ewha Authors
- 안정혁
- SCOPUS Author ID
- 안정혁
- Issue Date
- 2015
- Journal Title
- NATURE MEDICINE
- ISSN
- 1078-8956
1546-170X
- Citation
- NATURE MEDICINE vol. 21, no. 9, pp. 1054 - +
- Publisher
- NATURE PUBLISHING GROUP
- Indexed
- SCI; SCIE; SCOPUS
- Document Type
- Article
- 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:
- 의과대학 > 의학과 > Journal papers
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