알츠하이머 병 진단 및 치료에 있어서 glycogen synthase kinase (GSK)-3β의 역할에 대한 연구

Abstract

Glycogen synthase kinase 3 (GSK3) was discovered as a kinase involved in the regulation of glucose metabolism; two closely related isoforms (GSK3α and GSK3β) are expressed. The GSK3β isoform is highly expressed in neural tissue, where its expression is regulated during development. Many studies have shown that GSK3β plays a central role in both sporadic and familial forms of AD. Therefore, GSK3β inhibition is a testable, promising strategy for the treatment of AD. In the present studies, we pursued three lines of investigation regarding the role of GSK3β in AD. First, we investigated the neuroprotective effects of CoQ10 on amyloid beta25-35(Aβ25-35)-induced neurotoxicity in rat cortical neurons. Oxidative stress plays critical roles in the pathogenic mechanisms of several neurodegenerative disorders including AD, and considerable effort has been focused on antioxidants as potential treatment agents. CoQ10 is known to have powerful antioxidant effects. Therefore, primary cultured cortical neurons were treated with several concentrations of CoQ10 and/or Aβ25-35. CoQ10 protected neuronal cells against Aβ25-35-induced neurotoxicity, and these effects were blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor. Aβ25-35 increased free radical levels in rat cortical neurons, but CoQ10 ameliorated the increase. In addition, CoQ10 treatment of Aβ25-35-injured primary cultured cortical neurons increased expression levels of proteins related to cell survival and decreased the levels of proteins associated with cell death. These results suggest that the neuroprotective effects of CoQ10 are mediated through the inhibition of the oxidative stress response and activation of the PI3K-pGSK3β pathway. Next, we investigated the role of the PI3K-pGSK3β pathway in CoQ10-mediated restoration of neural stem cell (NSC) proliferation, which is inhibited by Aβ25-35. Neurogenesis in the adult brain mainly occurs in two specific regions: the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. Many studies have suggested that alterations in NSCs may be an important part of AD pathogenesis. To evaluate the effects of CoQ10 on Aβ25-35-inhibited proliferation of neural stem cells, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35. NSC proliferation decreased with Aβ25-35 treatment, but combined treatment with CoQ10 increased the proliferation of Aβ25-35-treated NSCs and significantly increased the expression of proteins related to cell survival. Lastly, we investigated whether the pattern of tau phosphorylation in cerebrospinal fluid (CSF) correlated with clinical factors in AD and suggested which patient groups were best suited for GSK3β inhibitor treatment. CSF was collected from a total of 28 AD patients, and the CSF findings were compared to clinical factors, including the CDR score, the K-NPI score and medial temporal atrophy. These findings suggest that early stage patients who have more severe behavioral and psychological symptoms and medial temporal atrophy also had advanced tauopathy and may not be suitable for GSK3β inhibitor treatment.