Cell Biology

A BACE-is for Therapy

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Science  05 Nov 2010:
Vol. 330, Issue 6005, pp. 732
DOI: 10.1126/science.330.6005.732-b

Amyloid beta (Aβ) peptides aggregate in the brains of patients with Alzheimer's disease (AD), forming the hallmark plaques associated with neurodegeneration. β-site APP-cleaving enzyme 1 (BACE1) cleaves the amyloid precursor protein (APP) to generate Aβ. Blocking BACE1 activity is an attractive therapeutic approach, but so far, no such inhibitors have been identified. BACE1 is naturally degraded by the neuron's ubiquitinproteasome machinery, which suggests that the proteins that prepare BACE1 for degradation may also be potential therapeutic targets. Gong et al. now report that the protein Fbx2 in mice, as part of the SCFFbx2-E3-ligase complex, targets BACE1 for proteasomal degradation by tagging it with ubiquitin. In a mouse model of AD, Fbx2 overexpression not only promoted BACE1 degradation and reduced Aβ production but also improved synaptic activity.

The authors further determined that the transcriptional coactivator PGC-1α increases the expression of Fbx2 in neurons and thus also proteosomal degradation of BACE1. Indeed, AD mouse model brains and postmortem brain samples from humans with AD showed reduced amounts of PGC-1α that correlated with a decrease in Fbx2 and an increase BACE1 expression. Thus, controlling BACE1 activity by manipulating Fbx2 expression in the brain may be an effective strategy for treating AD.

Aging Cell 9, 10.1111/j.1474-9726.2010.00632.x (2010).

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