Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models.
Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models.
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DOI：
10.1007/s12035-018-1195-5
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发表时间：
2019-03
影响因子：
5.1
通讯作者：
Persidsky Y
中科院分区：
文献类型：
--
作者：
Rom S;Zuluaga-Ramirez V;Gajghate S;Seliga A;Winfield M;Heldt NA;Kolpakov MA;Bashkirova YV;Sabri AK;Persidsky Y
糖尿病（DM）终末器官损伤是由微血管损害（包括糖尿病视网膜病变和肾病）引起的。认知障碍是1型和2型DM的一种众所周知的并发症;然而，其机制尚不清楚。我们假设血脑屏障（BBB）受损在DM认知功能下降中起关键作用。使用1型DM模型（注射链脲佐菌素的C57 BL/6小鼠）和2型DM模型（瘦素敲除肥胖db/db小鼠），我们显示了与高血糖症相关的增强的BBB渗透性和记忆丧失（Y-迷宫，水迷宫）。1型DM动物的分离微血管中的基因谱显示，与血管生成、炎症、血管收缩/血管舒张和血小板活化途径相关的54种基因的表达失调至少2倍（包括eNOS、TNFα、TGFβ1、VCAM-1、E-选择素、几种趋化因子和MMP 9）。此外，基因表达的幅度与1型DM动物的认知能力下降程度有关。2型DM db/db动物脑微血管中的基因分析显示与DM 1模型中相似的基因改变，有些甚至更大程度。来自DM小鼠的脑组织的神经病理学分析显示，与对照组相比，小胶质细胞活化，ICAM-1表达和周细胞覆盖减弱。在两种DM模型中，脑组织中的炎性基因均显著上调。综上所述，我们的研究结果表明，糖尿病体内模型中的血脑屏障损害及其与记忆缺陷、脑内皮细胞基因改变和神经炎症的相关性。预防血脑屏障损伤可能是预防糖尿病认知功能减退的一种新的治疗方法。
End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y-maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1 and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM.
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影响因子：
9.3
作者：
Heier M;Margeirsdottir HD;Gaarder M;Stensæth KH;Brunborg C;Torjesen PA;Seljeflot I;Hanssen KF;Dahl-Jørgensen K
通讯作者：
Dahl-Jørgensen K
DOI：
10.1186/cc10420
发表时间：
2011-08-26
期刊：
Critical care (London, England)
影响因子：
--
作者：
Arabi YM;Dehbi M;Rishu AH;Baturcam E;Kahoul SH;Brits RJ;Naidu B;Bouchama A
通讯作者：
Bouchama A
影响因子：
--
作者：
Hartz, Anika M. S.;Notenboom, Sylvia;Bauer, Bjoern
通讯作者：
Bauer, Bjoern
DOI：
10.3791/2920
发表时间：
2011-07-20
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Bromley-Brits, Kelley;Deng, Yu;Song, Weihong
通讯作者：
Song, Weihong
影响因子：
4.8
作者：
Hanford, LE;Enghild, JJ;Oury, TD
通讯作者：
Oury, TD