Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430, Morioka, Obu, Aichi, 474-8511, Japan.
Department of Aging Neurobiology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
J Neuroinflammation. 2021 Apr 3;18(1):86. doi: 10.1186/s12974-021-02135-w.
Subcortical ischemic vascular dementia, one of the major subtypes of vascular dementia, is characterized by lacunar infarcts and white matter lesions caused by chronic cerebral hypoperfusion. In this study, we used a mouse model of bilateral common carotid artery stenosis (BCAS) to investigate the role of B-cell translocation gene 2 (BTG2), an antiproliferation gene, in the white matter glial response to chronic cerebral hypoperfusion.
Btg2 mice and littermate wild-type control mice underwent BCAS or sham operation. Behavior phenotypes were assessed by open-field test and Morris water maze test. Brain tissues were analyzed for the degree of white matter lesions and glial changes. To further confirm the effects of Btg2 deletion on proliferation of glial cells in vitro, BrdU incorporation was investigated in mixed glial cells derived from wild-type and Btg2 mice.
Relative to wild-type mice with or without BCAS, BCAS-treated Btg2 mice exhibited elevated spontaneous locomotor activity and poorer spatial learning ability. Although the severities of white matter lesions did not significantly differ between wild-type and Btg2 mice after BCAS, the immunoreactivities of GFAP, a marker of astrocytes, and Mac2, a marker of activated microglia and macrophages, in the white matter of the optic tract were higher in BCAS-treated Btg2 mice than in BCAS-treated wild-type mice. The expression level of Gfap was also significantly elevated in BCAS-treated Btg2 mice. In vitro analysis showed that BrdU incorporation in mixed glial cells in response to inflammatory stimulation associated with cerebral hypoperfusion was higher in Btg2 mice than in wild-type mice.
BTG2 negatively regulates glial cell proliferation in response to cerebral hypoperfusion, resulting in behavioral changes.
皮质下缺血性血管性痴呆是血管性痴呆的主要亚型之一，其特征是腔隙性梗死和由慢性脑灌注不足引起的白质病变。在这项研究中，我们使用双侧颈总动脉狭窄（BCAS）小鼠模型来研究增殖抑制基因 B 细胞易位基因 2（BTG2）在慢性脑灌注不足引起的白质胶质反应中的作用。
Btg2 小鼠和同窝野生型对照小鼠接受 BCAS 或假手术。通过旷场试验和 Morris 水迷宫试验评估行为表型。分析脑组织的白质病变和胶质变化程度。为了进一步证实 Btg2 缺失对体外胶质细胞增殖的影响，我们在源自野生型和 Btg2 小鼠的混合胶质细胞中研究了 BrdU 掺入。
与未经 BCAS 处理的野生型小鼠相比，BCAS 处理的 Btg2 小鼠表现出更高的自发运动活性和更差的空间学习能力。尽管 BCAS 后野生型和 Btg2 小鼠的白质病变严重程度没有显著差异，但在视神经束的白质中，星形胶质细胞标志物 GFAP 和激活的小胶质细胞和巨噬细胞标志物 Mac2 的免疫反应性在 BCAS 处理的 Btg2 小鼠中高于 BCAS 处理的野生型小鼠。Gfap 的表达水平在 BCAS 处理的 Btg2 小鼠中也显著升高。体外分析表明，对与脑灌注不足相关的炎症刺激的混合胶质细胞中 BrdU 掺入在 Btg2 小鼠中高于野生型小鼠。
BTG2 负调控对脑灌注不足的胶质细胞增殖反应，导致行为变化。
