Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

Multiple roles of HDAC inhibition in neurodegenerative conditions.

Tau is a group of neuronal microtubule-associated proteins that are formed by alternative mRNA splicing and accumulate in neurofibrillary tangles in Alzheimer's disease (AD) brain. Tau plays a key role in regulating microtubule dynamics, axonal transport and neurite outgrowth, and all these functions of tau are modulated by site-specific phosphorylation. There is significant evidence that a disruption of normal phosphorylation events results in tau dysfunction in neurodegenerative diseases, such as AD, and is a contributing factor to the pathogenic processes. Indeed, the abnormal tau phosphorylation that occurs in neurodegenerative conditions not only results in a toxic loss of function (e.g. decreased microtubule binding) but probably also a toxic gain of function (e.g. increased tau-tau interactions). Although tau is phosphorylated in vitro by numerous protein kinases, how many of these actually phosphorylate tau in vivo is unclear. Identification of the protein kinases that phosphorylate tau in vivo in both physiological and pathological processes could provide potential therapeutic targets for the treatment of AD and other neurodegenerative diseases in which there is tau pathology.

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Tau phosphorylation in neuronal cell function and dysfunction

The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways

https://www.cell.com/neuron/pdf/S0896-6273(08)00956-2.pdf

Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis

Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder Although the underlying mechanism(s) of this mood stabilizer remains controversial, recent evidence linking lithium to neurotrophic/neuroprotective effects (Choi and Sung (2000) 1475, 225−230; Davies et al (2000) 351, 95−105) suggests novel benefits of this drug in addition to mood stabilization Here, we report that both lithium as well as valproic acid (VPA) inhibit β-amyloid peptide (Aβ) production in HEK293 cells stably transfected with Swedish amyloid precursor protein (APP)751 and in the brains of the PDAPP (APPV717F) Alzheimer's disease transgenic mouse model at clinically relevant plasma concentrations Both lithium and VPA are known to be glycogen synthase kinase-3 (GSK3) inhibitors Our studies reveal that GSK3β is a potential downstream kinase, which modulates APP processing because inhibition of GSK3 activity by either a dominant negative GSK3β kinase-deficient construct or GSK3β antisense ol

Pat Solenberg

Papers

Lithium, a Common Drug for Bipolar Disorder Treatment, Regulates Amyloid-β Precursor Protein Processing