| First Author | Ly PT | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 1 | Pages | 224-35 |
| PubMed ID | 23202730 | Mgi Jnum | J:194181 |
| Mgi Id | MGI:5471172 | Doi | 10.1172/JCI64516 |
| Citation | Ly PT, et al. (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123(1):224-35 |
| abstractText | Deposition of amyloid beta protein (Abeta) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Abeta is generated from sequential cleavages of the beta-amyloid precursor protein (APP) by the beta- and gamma-secretases, and beta-site APP-cleaving enzyme 1 (BACE1) is the beta-secretase essential for Abeta generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating gamma-secretase activity, thereby facilitating Abeta production. There are two highly conserved isoforms of GSK3: GSK3alpha and GSK3beta. We now report that specific inhibition of GSK3beta, but not GSK3alpha, reduced BACE1-mediated cleavage of APP and Abeta production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3beta was dependent on NF-kappaB signaling. Inhibition of GSK3 signaling markedly reduced Abeta deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3beta and that inhibition of GSK3 signaling can reduce Abeta neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the beta-isoform of GSK3 may be a safe and effective approach for treating AD. |
