GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals

Abstract

The dysregulation of glycogen synthase kinase-3 (GSK3) has been implicated in Alzheimer disease (AD) pathogenesis and in Aβ-induced neurotoxicity, leading us to investigate it as a therapeutic target in an intracerebroventricular Aβ infusion model. Infusion of a specific GSK3 inhibitor SB216763 (SB) reduced a downstream target, phospho-glycogen synthase 39%, and increased glycogen levels 44%, suggesting effective inhibition of enzyme activity. Compared to vehicle, Aβ increased GSK3 activity, and was associated with elevations in levels of ptau, caspase-3, the tau kinase phospho-c-jun N-terminal kinase (pJNK), neuronal DNA fragmentation, and gliosis. Co-infusion of SB corrected all responses to Aβ infusion except the induction of gliosis and behavioral deficits in the Morris water maze. Nevertheless, SB alone was associated with induction of neurodegenerative markers and behavioral deficits. These data support a role for GSK3 hyperactivation in AD pathogenesis, but emphasize the importance of developing inhibitors that do not suppress constitutive activity.

Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

“…Overexpression of GSK-3 induces cell death and its inhibition is protective (Miura and Miki 2009). As several studies have shown that administration of a GSK-3b inhibitor can protect cultured neurons against excitotoxicity and toxin-induced apoptosis (Liang and Chuang 2007;Chuang et al 2011), and reduce the presence of pyknotic neurons in a model of Alzheimer's disease (Hu et al 2009), we questioned if similar benefits could be observed following stroke by using the potent and selective GSK-3b Figure 2. Neuroprotection was seen with delayed treatment with a GSK-3b inhibitor.…”

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

“…5 However, it is neither a potent nor specific inhibitor of GSK-3. 94 In fact, neuronal deficits have been reported to result from both genetic reduction and specific inhibition of GSK-3, 95,96 highlighting the risk of inhibiting this enzyme. 97 Lithium arrests neuropathology in some AD rodent models, 36,38,39 but these are aggressive models driven by transgene overexpression, where the benefits of lithium inhibiting a dominant pathological target (for example, tau hyperphosphorylation) outweigh lithium-induced neurotoxicity.…”

-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin

“…In peripheral tissues, both JNK and ERK phosphorylate IRS-1 at Ser307 (rodent equivalent for human Ser312) (Aguirre et al, 2000) and Ser616 (D'Alessandris et al, 2007). The resulting loss of IRS-1 coupling to PI3-K/Akt is predicted to activate another major tau kinase, GSK3␤, which is known to be activated by A␤ (Takashima et al, 1996;Ma et al, 2006;Hu et al, 2009). This process further dysregulates insulin signaling since GSK3 itself directly phosphorylates IRS-1 at Ser332 to help inactivate IRS-1 (Liberman and Eldar-Finkelman, 2005).…”