GSK3 and Alzheimer’s disease: facts and fiction…

Abstract

The physiological functions and pathological roles of the Glycogen synthase kinase-type 3 (GSK3) kinases in peripheral and central systems are diverse and complex, and therefore hard to unravel in molecular detail in vivo. Our assignment to review and discuss available data to clarify the actual position of these kinases in the pathology of Alzheimer’s dementia (AD) was both ambitious and easy. On the one hand, numerous studies are available in isolated, recombinant, or cell-based systems, which have resulted in very diverse data-sets that are hardly informative for the brain in vivo. At the other extreme, reliable, and relevant models for the role of GSK3 in CNS are rare, if not lacking. Moreover, (too) many in vivo studies used Li+ as “specific” inhibitor of GSK3, which is factually not valid because lithium ions are neither specific nor potent inhibitors of GSK3 in vivo. More specific pharmacological inhibitors of GSK3 have met with considerable problems, and are reviewed by others in this issue or elsewhere. We concentrate here on AD-related aspects of GSK3 in brain in vivo, mainly studied in transgenic mice and highlight some of the more important issues, among many remaining: activation of GSK3 by amyloid, phosphorylation of protein tau, effects on or interference with synaptic activity, differentiation between both GSK3 isoforms. These relate directly to brain function, and brain dysfunction in AD, and are to be resolved if we want to understand the molecular pathology of this dreadful disease.

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

“…However, lithium chloride has long been used clinically for the treatment of bipolar disorder, and its chronic administration has not been associated with increased cancer risk (32). GSK3 inhibitors have also been shown to be promising therapeutic agents in a number of preclinical studies for Alzheimer's disease and diabetes (33,34). Inhibition of GSK3 in a preclinical model of mixed lymphocytic leukemia effectively suppressed tumor growth and prolonged survival (35).…”

β-N-methylamino-L-alanine induces changes in both GSK3 and TDP-43 in human neuroblastoma

“…In addition, it has been described an increased level of GSK3β expression in frontal and temporal cortex in ALS with cognitive impairment (Yang et al, 2008). This enzyme is involved in normal and pathological tau phosphorylation (Balaraman et al, 2006) and it can play a role in AD pathogenesis (Kremer et al, 2011).…”

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.…”