Inhibition of GSK3?-mediated BACE1 expression reduces Alzheimer-associated phenotypes.

ABSTRACT: Deposition of amyloid ? protein (A?) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). A? is generated from sequential cleavages of the ?-amyloid precursor protein (APP) by the ?- and ?-secretases, and ?-site APP-cleaving enzyme 1 (BACE1) is the ?-secretase essential for A? generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating ?-secretase activity, thereby facilitating A? production. There are two highly conserved isoforms of GSK3: GSK3? and GSK3?. We now report that specific inhibition of GSK3?, but not GSK3?, reduced BACE1-mediated cleavage of APP and A? production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3? was dependent on NF-?B signaling. Inhibition of GSK3 signaling markedly reduced A? 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 GSK3? and that inhibition of GSK3 signaling can reduce A? neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the ?-isoform of GSK3 may be a safe and effective approach for treating AD.

SUBMITTER: Ly PT 

PROVIDER: S-EPMC3533290 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature