Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.
Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.nbd.2016.05.015
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发表时间：
2016-09
影响因子：
6.1
通讯作者：
Deane R
中科院分区：
文献类型：
--
作者：
Peng W;Achariyar TM;Li B;Liao Y;Mestre H;Hitomi E;Regan S;Kasper T;Peng S;Ding F;Benveniste H;Nedergaard M;Deane R
脑淋巴转运，定义为脑脊髓液（CSF）动脉周围流入大脑，和间质液（ISF）清除，在老化的大脑中减少。然而，胶质淋巴转运是否影响阿尔茨海默病（AD）中可溶性Aβ的分布尚不清楚。在野生型小鼠中，我们发现Aβ40（荧光标记的Aβ40或未标记的Aβ40）通过动脉周围空间从CSF分布到大脑，并与神经元相关。相比之下，Aβ42主要局限于动脉周围空间，这主要是因为与Aβ40相比，其更容易发生寡聚化。有趣的是，在CSF中用Aβ40预处理，而不是Aβ42，减少了CSF向脑中的转运。在APP/PS1小鼠（AD模型，有和无广泛淀粉样蛋白-β沉积）中，由于毒性Aβ物质（如可溶性低聚物）的蓄积，胶质淋巴转运减少。CSF源性Aβ40与现有内源性血管和实质淀粉样β斑块共定位，因此可能有助于脑淀粉样血管病和实质Aβ蓄积的进展。重要的是，胶质淋巴衰竭先于显著的淀粉样蛋白-β沉积，因此，可能是AD的早期生物标志物。通过扩展，恢复胶质淋巴流入和ISF清除是减缓AD发作和进展的潜在治疗靶点。
Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer’s disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.