Document Detail


β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease.
MedLine Citation:
PMID:  23202293     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
β-arrestins are associated with numerous aspects of G protein-coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2(-/-) mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ(40) and Aβ(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β(2)-adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.
Authors:
Amantha Thathiah; Katrien Horré; An Snellinx; Elke Vandewyer; Yunhong Huang; Marta Ciesielska; Gerdien De Kloe; Sebastian Munck; Bart De Strooper
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-02
Journal Detail:
Title:  Nature medicine     Volume:  19     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-08     Completed Date:  2013-03-06     Revised Date:  2013-03-20    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  43-9     Citation Subset:  IM    
Affiliation:
Vlaams Instituut voor Biotechnologie Center for the Biology of Disease, Leuven, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / metabolism*
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / biosynthesis*
Animals
Arrestins / genetics,  metabolism*
CHO Cells
Cell Line
Cricetinae
HEK293 Cells
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Adrenergic, beta-2 / metabolism*
Receptors, G-Protein-Coupled / metabolism
Signal Transduction
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Arrestins; 0/GPR3 protein, mouse; 0/Receptors, Adrenergic, beta-2; 0/Receptors, G-Protein-Coupled; 0/beta-arrestin; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections
Comment In:
Nat Rev Neurol. 2013 Feb;9(2):60   [PMID:  23318295 ]
Nat Med. 2013 Jan;19(1):22-4   [PMID:  23296004 ]

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