Journal
AGING CELL
Volume 9, Issue 6, Pages 1018-1031Publisher
WILEY
DOI: 10.1111/j.1474-9726.2010.00632.x
Keywords
Alzheimer's disease; BACE1; Fbx2; synaptic function
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Funding
- NIH [NS-15076]
- Columbia ADRC [AG-008702]
- US National Institutes of Health
- Alzheimer's Association [IIRG-07-59856, IIRG-08-89354]
- Grants-in-Aid for Scientific Research [21580121] Funding Source: KAKEN
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P>BACE1 (beta-secretase) plays a central role in the beta-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCFFbx2-E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and beta-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced beta-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPAR gamma coactivator-1 alpha (PGC-1 alpha) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1 alpha was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing beta-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.
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