Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

VR Venna, SE Benashski, A Chauhan… - Learning & …, 2015 - learnmem.cshlp.org
VR Venna, SE Benashski, A Chauhan, LD McCullough
Learning & Memory, 2015learnmem.cshlp.org
Memory deficits are common among stroke survivors. Identifying neuroprotective agents that
can prevent memory impairment or improve memory recovery is a vital area of research.
Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular
signaling pathways. Unlike many other kinases, GSK-3β is active only when
dephosphorylated and activation promotes inflammation and apoptosis. In contrast,
increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition …
Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3β is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition has beneficial effects on memory in other disease models. GSK-3β regulates both the 5′AMP-activated kinase (AMPK) and transforming growth factor-β-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3β inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-α2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3β inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3β inhibition were seen in AMPK deficient mice. However, GSK-3β inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3β. Targeting GSK-3β could be a novel therapeutic strategy for post-stroke cognitive deficits.
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