Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice.
Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice.
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DOI：
10.1186/s13195-022-00999-5
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发表时间：
2022-04-26
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影响因子：
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淀粉样蛋白β(Aβ)清除缓慢被认为是阿尔茨海默病(AD)Aβ斑块形成的基础。β的部分清除是通过淋巴系统进行的，这是一个全脑范围的血管周围通路网络，支持脑脊液和脑间质液体的交换。淋巴清除，或血管周围脑脊液-间质液体交换，依赖于星形胶质细胞水通道蛋白4(AQP4)，因为在小鼠中，水通道蛋白4的缺失减缓了血管周围交换，损害了Aβ清除，并促进了Aβ斑块的形成。为了确定AQP4在人类AD中的作用，我们在一个人类尸检病例系列中评估了AQP4的表达和定位。然后，我们使用缺乏血管周围α定位的AQP4基因敲除小鼠模型来评估血管周围AQP4定位缺失对淋巴脑脊液示踪剂分布的影响。最后，我们跨越这条线进入淀粉样变性小鼠模型(Tg2576小鼠)，以评估水通道蛋白4定位对淀粉样蛋白β水平的影响。在尸检病例系列中，我们观察到，与认知正常的受试者相比，AD受试者额叶皮质灰质中AQP4的血管周围定位减少。这种血管周围水通道蛋白4定位的下降与Aβ和神经原纤维病理负担的增加以及痴呆发病前认知能力的下降有关。在啮齿动物研究中，Snta1基因缺失减缓了脑脊液示踪剂流入和间质示踪剂流出小鼠大脑的速度，并增加了淀粉样蛋白β的水平。这些发现表明，血管周围AQP4定位的缺失可能参与了人类AD病理的发展。网上版载有补充材料，可在10.1186/s13195-022-00999-5查阅。
Slowed clearance of amyloid β (Aβ) is believed to underlie the development of Aβ plaques that characterize Alzheimer’s disease (AD). Aβ is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aβ clearance, and promotes Aβ plaque formation. To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin (Snta1) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid β levels. In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aβ and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid β levels. These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations. The online version contains supplementary material available at 10.1186/s13195-022-00999-5.
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DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
DOI：
10.1074/jbc.m115.646034
发表时间：
2015-07-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kitchen P;Day RE;Taylor LH;Salman MM;Bill RM;Conner MT;Conner AC
通讯作者：
Conner AC
影响因子：
6.2
作者：
Lange, Jenny;Gillham, Olivia;Ferretti, Patrizia
通讯作者：
Ferretti, Patrizia
影响因子：
17.1
作者：
Iliff JJ;Wang M;Liao Y;Plogg BA;Peng W;Gundersen GA;Benveniste H;Vates GE;Deane R;Goldman SA;Nagelhus EA;Nedergaard M
通讯作者：
Nedergaard M
影响因子：
3.3
作者：
Igarashi, Hironaka;Huber, Vincent J.;Tsujita, Mika;Nakada, Tsutomu
通讯作者：
Nakada, Tsutomu