Reticulon family members modulate BACE1 activity and amyloid-β peptide generation

被引:230
作者
He, WX
Lu, YF
Qahwash, I
Hu, XY
Chang, AS
Yan, RQ
机构
[1] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA
[2] Pharmacia Corp, Kalamazoo, MI 49007 USA
关键词
D O I
10.1038/nm1088
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inhibiting the activity of the beta-amyloid converting enzyme 1 (BACE1) or reducing levels of BACE1 in vivo decreases the production of amyloid-beta. The reticulon family of proteins has four members, RTN1, RTN2, RTN3 and RTN4 (also known as Nogo), the last of which is well known for its role in inhibiting neuritic outgrowth after injury. Here we show that reticulon family members are binding partners of BACE1. In brain, BACE1 mainly colocalizes with RTN3 in neurons, whereas RTN4 is more enriched in oligodendrocytes. An increase in the expression of any reticulon protein substantially reduces the production of Abeta. Conversely, lowering the expression of RTN3 by RNA interference increases the secretion of Abeta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein. Thus, changes in the expression of reticulon proteins in the human brain are likely to affect cellular amyloid-beta and the formation of amyloid plaques.
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页码:959 / 965
页数:7
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