GSK‐3: A key player in neurodegeneration and memory

Abstract

Abnormalities in molecular signalling have been implicated in neurodegeneration. It is emerging that glycogen synthase kinase‐3 (GSK‐3) is a key signalling molecule that induces neurodegeneration and deficits in memory formation related to Alzheimer's disease (AD). Early stages of AD are associated with deficits in memory formation before neuronal cell death is detectable. Recent studies in rodents have suggested that these impairments in memory formation might result from increased GSK‐3 signalling, because enhanced GSK‐3 activity impairs hippocampal memory formation. GSK‐3 activity blocks synaptic long‐term potentiation and induces long‐term depression. Furthermore, increased GSK‐3 signalling is likely to be a key contributor to the formation of the pathological hallmarks in AD, neurofibrillary tangles (NFTs) and amyloid plaques. Recent studies with mouse models have indicated that GSK‐3, but not cyclin‐dependent kinase 5, is critical for hyperphosphorylation of the cytoskeletal protein tau, which is the prerequisite for NFT formation in AD. Furthermore, increased GSK‐3 signalling in AD mice causes abnormal processing of the amyloid precursor protein so that amyloid peptide production augments and neurotoxicity is induced. Taken together, the current evidences suggest that increased GSK‐3 signalling may be responsible for the deficits in memory formation in early stages of AD and neurodegeneration in later stages of the disease. © 2009 IUBMB IUBMB Life 61(5): 516–521, 2009

Amyloid- Peptide Oligomers Disrupt Axonal Transport through an NMDA Receptor-Dependent Mechanism That Is Mediated by Glycogen Synthase Kinase 3 in Primary Cultured Hippocampal Neurons

“…Notably, synaptic modulation and changes in transport are linked (Schlager and Hoogenraad, 2009), and thus perturbing synaptic activity might have a direct effect on transport. Although the mechanism of action of A␤Os at the plasma membrane is not known specifically, A␤Os can modulate NMDA and insulin receptors , 2009. To determine whether A␤O-induced NMDAR dysfunction and transport impairment were mechanistically coupled, hippocampal neurons were treated with two NMDAR channel blockers and a competitive antagonist before A␤O treatment.…”

“…GSK-3␤ is of particular interest, as it can be activated by fibrillar forms of A␤, and active GSK-3␤ is found in neurofibrillary tangles (NFTs) in postmortem AD brains (Giese, 2009). GSK-3␤ activation by fibrillar A␤ has been implicated in disruption of mitochondrial transport in primary neurons (Rui et al, 2006).…”

The roles of protein kinases in learning and memory

“…Another important PI3K/Akt target is glycogen synthase kinase 3b (GSK-3b) (for review, see Giese 2009). Akt phosphorylation at serine-9 (S9) inhibits GSK-3b activity.…”

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

“…The hyperphosphorylation of Tau is probably the most extensively studied area in the field of neurodegenerative disease. To date, more than 39 phosphorylation sites have been detected in PHF-Tau, including multiple proline-directed serine/threonine residues (69,70). The level of Tau phosphorylation (7-10 phosphorylations per mole of Tau) is regulated dynamically by several kinases and phosphatases.…”