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Upregulation of GSK3? Contributes to Brain Disorders in Elderly REG?-knockout Mice.

ABSTRACT: GSK3? regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3? protein stability remain ambiguous. REG?, an important proteasome activator for ubiquitin-independent protein degradation, has been shown to degrade certain intact proteins and is involved in the regulation of important biological processes. Here we demonstrate that REG? promotes the degradation of GSK3? protein in vitro and in vivo. With increased GSK3? activity, REG? knockout (REG?-/-) mice exhibit late-onset sensorimotor gating and cognitive deficiencies including decreased working memory, hyperlocomotion, increased stereotype, defective prepulse inhibition (PPI), and disability in nest building, at the age of 8 months or older. Inhibition of GSK3? rescued the compromised PPI phenotypes and working memory deficiency in the knockout mice. Also, we found an age-dependent decrease in the trypsin-like proteasomal activity in REG?-/- mice brains, which may be reflective of a lack of degradation of GSK3?. Collectively, our findings reveal a novel regulatory pathway in which the REG?-proteasome controls the steady-state level of GSK3? protein. Dysfunction in this non-canonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice.

SUBMITTER: Lv Y

PROVIDER: S-EPMC4793118 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice.

Lv Yiqing Y Meng Bo B Dong Hao H Jing Tiantian T Wu Nan N Yang Yingying Y Huang Lan L Moses Robb E RE O'Malley Bert W BW Mei Bing B Li Xiaotao X

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150915 5

GSK3β regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3β protein stability remain ambiguous. REGγ, an important proteasome activator for ubiquitin-independent protein degradation, has been shown to degrade certain intact proteins and is involved in the regulation of important biological processes. Here we demonstrate that REGγ promotes the degradation of GSK3β protein in vitro and in vivo. With increased GSK3β activity, REGγ knockout (REGγ-/-) mice exh ...[more]

PMID: 26370326

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Project description:BackgroundPerioperative neurocognitive disorders (PND) occur frequently after surgery, especially in aged patients. Surgery-induced neuroinflammation and blood-brain barrier (BBB) dysfunction play a crucial role in the pathogenesis of PND. Interleukin-17A (IL-17A) increases after surgical stress and will be involved in BBB dysfunction. However, the effect of IL-17A on BBB function during PND remains poorly understood.MethodsMale wild-type C57BL/6J mice (15 months old) received tibial fracture surgery and fixation to establish the PND model. All the mice were injected intraperitoneally with an IL-17A-neutralizing antibody (Abs) or isotype-control Abs 30 min before tibial fracture surgery. Animal behaviour tests conducted 24 h after surgery included the contextual fear conditioning and Y maze tests. Serum and hippocampus IL-17A levels and hippocampus IL-6 and IL-1β levels were detected by ELISA. BBB function was detected by Evans blue (EB) test. Hippocampus matrix metalloproteinase-2 (MMP-2)- and MMP-9-positive cells were detected by immunohistochemistry. Hippocampus albumin, occludin, claudin-5 and IL-17A receptors were detected by Western blot. For the in vitro experiment, bEnd.3 cells were incubated with IL-17A. Cell IL-17A receptors were detected by immunofluorescence. Cellular MMP-2, MMP-9, occludin, and claudin-5 were detected by Western blot.ResultsTibial fracture surgery promoted memory impairment, increased levels of IL-17A and IL-17A receptors, inflammatory factor production and BBB dysfunction. IL-17A Abs inhibited this effect, including improving memory function, decreasing inflammatory factor production and alleviating BBB disruption, indicated by decreased tight junctions (TJs) and increased MMPs after surgery. The in vitro study suggested that recombinant IL-17A could upregulate the expression of IL-17A receptors, decrease TJs and increase the level of MMPs in bEnd.3 cells.ConclusionsOur results suggested that IL-17A-promoted BBB disruption might play an important role in the pathogenesis of PND.

Dataset Information

Upregulation of GSK3? Contributes to Brain Disorders in Elderly REG?-knockout Mice.

Publications

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice.

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