Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation

Abstract

Summary It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

Transmission of Alzheimer's Disease-Associated Microbiota Dysbiosis and its Impact on Cognitive Function: Evidence from Mouse Models and Human Patients

“…The present study de ned this hypothesis by showing that WT mice co-housed with AD Tg mice, referred to as AD-exposed WT (ADWT) mice, acquired ADrelated gut microbiota dysbiosis and developed AD pathogenesis and cognitive impairment. The study also revealed that the mechanism underlying this effect that butyric acid, a short-chain fatty acid produced by GMB, mediated acetylation-regulated phosphorylation in GSK3β, a kinase known to be involved in the phosphorylation of Tau (51,52). Additionally, our clinically relevant studies indicated that the partners of AD patients (PAD) also acquired GMB pro les similar to AD patients, but distinct from non-AD controls (CON).…”

GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer’s disease-like amyloid strain

“…The proline-directed serine/threonine kinase GSK3β is closely associated with the pathological phosphorylation of tau in AD [37][38][39] . In AD patients, GSK3β co-localizes with neurofibrillary tangles 40,41 and concentrates in the frontal cortex of AD brains 38 .…”

Novel Therapies for Parkinsonian Syndromes–Recent Progress and Future Perspectives

“…GSK-3 inhibition leads to increased stem cell propagation and neuronal differentiation (Morales-Garcia et al, 2012). Mice with reduced GSK-3β expression show altered synapse condition and lower tau accumulation (Amaral et al, 2021). Another study conducted on mice demonstrated that blocking GSK-3 signaling with tideglusib (thiadiazolidinone) decreases tau phosphorylation and prevents memory deficits in an AD mouse model (Serenó et al, 2009).…”