GSK-3β, a pivotal kinase in Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.

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

“…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).…”

Glycogen Synthase Kinase 3β-mediated Phosphorylation in the Most C-terminal Region of Protein Interacting with C Kinase 1 (PICK1) Regulates the Binding of PICK1 to Glutamate Receptor Subunit GluA2

“…For example, A␤ facilitates GSK-3␤ signaling (19,20), and tau is a well known substrate of GSK-3␤ (21,22). GSK-3␤ is regarded as a critical molecular link between A␤ and tau (23). Interestingly, GSK-3␤ is required for LTD (24).…”

Alzheimer’s disease as an inflammatory disease

“…Tau hyperphosphorylation could be toxic, independently if it forms toxic aggregates or could remain in soluble form (76). In this way, tau toxicity could result in an inflammatory process that could be prevented by the inhibition of tau kinases, like GSK3 (77).…”