Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment.
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment.
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DOI：
10.3389/fnagi.2021.788519
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发表时间：
2021
影响因子：
4.8
通讯作者：
Horsburgh K
中科院分区：
文献类型：
--
作者：
Li M;Kitamura A;Beverley J;Koudelka J;Duncombe J;Lennen R;Jansen MA;Marshall I;Platt B;Wiegand UK;Carare RO;Kalaria RN;Iliff JJ;Horsburgh K
大血管疾病和颈动脉狭窄是导致血管性认知障碍（VCI）和痴呆的关键机制。我们以前的工作，以及其他人的工作，使用啮齿动物模型，证明双侧颈总动脉狭窄（BCAS）通过神经胶质血管单位的逐渐恶化和淀粉样β（Aβ）蛋白的积累导致认知障碍。由于用于废物清除（包括Aβ清除）的全脑引流途径（胶质淋巴）通过神经胶质机制参与了VCI的病理生理学，因此我们假设胶质淋巴功能在BCAS模型中受损，并在Aβ存在时加重。对雄性野生型和Tg-SwDI（微血管淀粉样蛋白模型）小鼠进行BCAS或假手术，这导致脑灌注减少和空间学习获得和认知灵活性受损。生存3个月后，通过脑脊液（CSF）荧光示踪剂内流评价胶质淋巴功能。我们证明，BCAS引起了显着的区域减少脑脊液示踪剂流入的背外侧皮质和CA 1-DG分子层。与这些变化平行，在BCAS后观察到反应性星形胶质细胞增生增加。为了进一步研究可能导致这些变化的机制，我们测量了皮质血管的搏动。BCAS损害WT和Tg-SwDI小鼠软脑膜动脉的血管脉动。我们的研究结果表明，BCAS影响VCI，这是由受损的胶质淋巴引流和减少血管搏动。我们建议在治疗VCI时需要考虑这些额外的靶点。
Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.
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影响因子：
29
作者：
Ding J;Sigurðsson S;Jónsson PV;Eiriksdottir G;Charidimou A;Lopez OL;van Buchem MA;Guðnason V;Launer LJ
通讯作者：
Launer LJ
DOI：
10.1111/chf.12025
发表时间：
2013-07
期刊：
Congestive heart failure (Greenwich, Conn.)
影响因子：
--
作者：
Alosco ML;Brickman AM;Spitznagel MB;Garcia SL;Narkhede A;Griffith EY;Raz N;Cohen R;Sweet LH;Colbert LH;Josephson R;Hughes J;Rosneck J;Gunstad J
通讯作者：
Gunstad J
DOI：
10.1001/jama.2017.3090
发表时间：
2017-04-11
期刊：
JAMA
影响因子：
--
作者：
Gottesman RF;Schneider AL;Zhou Y;Coresh J;Green E;Gupta N;Knopman DS;Mintz A;Rahmim A;Sharrett AR;Wagenknecht LE;Wong DF;Mosley TH
通讯作者：
Mosley TH
影响因子：
4.8
作者：
Gupta A;Iadecola C
通讯作者：
Iadecola C
影响因子：
168.9
作者：
Esiri, MM;Nagy, Z;Smith, AD
通讯作者：
Smith, AD