Activation of GSK‐3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats

Abstract

The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse‐3 (GSK‐3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK‐3 by lateral ventricular infusion of wortmannin (WT) and GF‐109203X (GFX), the inhibitors of phosphoinositol‐3 kinase (PI3‐K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor‐κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK‐3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK‐3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.

Hibernation Impairs Odor Discrimination – Implications for Alzheimer’s Disease

“…It is possible that phosphorylation of tau in torpor is associated with a cholinergic deficit during the arousal phase. Such disruption cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex has been observed by activation of a major tau kinase, GSK3β (Wang et al, 2017). This might explain the observed impairment of olfactory discrimination in hibernation and perhaps in the very early, preclinical stages of Alzheimer’s disease (Attems and Jellinger, 2006; Attems et al, 2014; Roberts et al, 2016).…”

Small-Molecule SB216763-Loaded Microspheres Repair Peripheral Nerve Injury in Small Gap Tubulization

“…Glycogen synthase kinase-3β has a wide range of cellular functions, including cell death, cell cycle, carcinogenesis, and autophagy, and it is considered an important regulator of various signal transduction pathways, including the Wnt pathway (Bhat et al, 2000; Forde and Dale, 2007; Park et al, 2013). GSK3β has also become an important drug target in anticancer therapy (Kingwell, 2018), Obesity-Induced White Adipose Tissue Inflammation (Wang et al, 2018), diabetes (Mussmann et al, 2007), and central nervous system diseases (Wang et al, 2017; Wickens et al, 2017).…”

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“…As CREB is a critical transcriptional factor involved in synapse and cognitive functions, our data reveal a novel mechanism underlying tau-induced synapse impairments and cognitive deficits. Additionally, tau accumulation can mutually activate GSK-3β [ 1 ] and disrupts axonal transport in cholinergic neurons [ 21 ].…”

“…The pharmacological activation of GSK-3 significantly decreases the acetylcholine level via inhibition of choline acetyl transferase rather than regulating acetylcholinesterase, while inhibition of GSK-3 by LiCl or SB216763 rescues the cholinergic functions. These data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients [ 21 ].…”