Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Abstract

Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β-and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ 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 GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis

“…As blockade of this AMPAR endocytosis has no effect on either basal synaptic transmission or the induction of LTP, our results support the notion that this AMPAR endocytosis may represent a feedback mechanism secondary to the increased synaptic efficacy during LTP. Although the mechanisms by which increased synaptic efficacy activates such a secondary AMPAR endocytosis are still unclear, Hou et al and others have recently reported a novel input-specific homeostatic downregulation of synaptic genic mice (referred to herein as AD mice) (36,37). As shown in Figure 6A, fEPSP recordings in vivo revealed that sHFS could only induce a decaying LTP that lasted for less than 1 hour in AD mice (aged 2.5 months) receiving control peptide infusion (scrGluA2 3Y , 3 μmol/kg, i.p.)…”

“…The other half of the brains was fixed in freshly depolymerized 4% paraformaldehyde and sectioned with a Cryostat (Leica) to 30-μm thickness for immunocytochemical staining as previously described (36,37). Every sixth slice with the same reference position was mounted onto slides for staining.…”

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

“…Recent data have also emphasized this possibility by showing that PKA stimulation using a cAMP phosphodiesterase inhibitor leads to an inhibition of GSK3␤ activity and attenuates A␤-induced tauopathy (72). GSK3␤ has also been shown to regulate A␤ production in vivo by controlling BACE-1 gene expression in a NFB-dependent manner (15); therefore, the inhibition of GSK3␤ activity following Syk inhibition may also contribute to the inhibition of A␤ and BACE-1 expression observed following Syk inhibition. Alternatively, Syk inhibition may also result in a suppression of NFB activation via an inhibition of RAF phosphorylation and AKT phosphorylation, which consequently is expected to lower BACE-1 expression and A␤ production.…”

“…Cdk5 has been shown to indirectly affect Tau hyperphosphorylation by regulating GSK3␤ activity establishing GSK3␤ as a key mediator of Tau phosphorylation at diseaseassociated sites (12). GSK3␤ appears to be a pivotal enzyme in AD as it regulates A␤ production and mediates pathological Tau hyperphosphorylation induced by A␤ (15)(16)(17).…”

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

“…34 The inhibition of GSK-3b reduces the bsite APP cleaving enzyme 1-mediated cleavage of APP through a NF-jB signaling-mediated mechanism, which subsequently reduces Ab neuropathology and alleviates memory deficits in AD model mice. 35 In addition, the pathological activation of GSK-3b has been reported to induce apoptosis and is inhibited by phosphorylation. 36 Therefore, the up-regulation of p-GSK-3b inhibits its kinase's activity, and this may confer a protective effect on AD.…”