High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer's disease associated with chronic platelet activation.
High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer's disease associated with chronic platelet activation.
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高脂肪饮食诱导的动脉粥样硬化会促进与慢性血小板活化相关的阿尔茨海默病三重转基因 (3 × Tg) 小鼠模型中的神经变性
DOI：
10.1186/s13195-021-00890-9
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发表时间：
2021-08-28
期刊：
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Wang M;Lv J;Huang X;Wisniewski T;Zhang W
流行病学研究将动脉粥样硬化、高血压和糖尿病等血管疾病危险因素与阿尔茨海默病 (AD) 联系起来。这些情况与 β-淀粉样蛋白 (Aβ) 聚集和 tau 病理学之间是否存在直接联系尚不确定。为了研究动脉粥样硬化与 AD 病理学之间可能存在的联系，我们让三重转基因 (3 × Tg) AD 小鼠在 3 个月大时接受高脂肪饮食 (HFD)，这相当于人类的成年早期。治疗 9 个月后，HFD 治疗的 3 × Tg 小鼠表现出更严重的记忆缺陷，并伴有血液高凝、血小板增多和慢性血小板活化。 HFD 处理的 3 × Tg 小鼠的促凝血血小板主动诱导可溶性 Aβ40 转化为纤维状 Aβ 聚集体，与整合素 αIIbβ3 和凝聚素表达增加相关。在 9 个月及以上时，观察到血小板相关纤维状 Aβ 聚集物会阻塞 HFD 治疗的 3 × Tg 小鼠的脑血管。 HFD 治疗的 3 × Tg 小鼠表现出更大的脑淀粉样血管病 (CAA) 负担和脑血管通透性增加，以及更广泛的神经炎症、tau 蛋白过度磷酸化和神经元损失。用人源化 GPIIIa49-66 scFv Ab (A11) 解聚预先存在的血小板微凝块，可在体外显着减少血小板相关纤维状 Aβ 聚集，并改善体内血管通透性。这些发现表明，动脉粥样硬化对 AD 病理学的主要贡献是通过其对血液凝固和血小板介导的 Aβ 聚集体形成的影响，从而损害脑血流量，从而损害神经元功能。这会导致认知能力下降。在线版本包含可在 10.1186/s13195-021-00890-9 获取的补充材料。
Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer’s disease (AD). Whether there are direct links between these conditions to β-amyloid (Aβ) aggregation and tau pathology is uncertain. To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aβ40 into fibrillar Aβ aggregates, associated with increased expression of integrin αIIbβ3 and clusterin. At 9 months and older, platelet-associated fibrillar Aβ aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aβ aggregates in vitro and improved vascular permeability in vivo. These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aβ aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline. The online version contains supplementary material available at 10.1186/s13195-021-00890-9.
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影响因子：
4.6
作者：
Gaspar RS;Unsworth AJ;Al-Dibouni A;Bye AP;Sage T;Stewart M;Wells S;Cox RD;Gibbins JM;Sellayah D;E Hughes C
通讯作者：
E Hughes C
DOI：
10.1186/s13195-017-0328-9
发表时间：
2017-12-29
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Bos I;Verhey FR;Ramakers IHGB;Jacobs HIL;Soininen H;Freund-Levi Y;Hampel H;Tsolaki M;Wallin ÅK;van Buchem MA;Oleksik A;Verbeek MM;Olde Rikkert M;van der Flier WM;Scheltens P;Aalten P;Visser PJ;Vos SJB
通讯作者：
Vos SJB
影响因子：
4.8
作者：
Canobbio, Ilaria;Visconte, Caterina;Torti, Mauro
通讯作者：
Torti, Mauro
影响因子：
14
作者：
通讯作者：
--
影响因子：
3.8
作者：
Kucheryavykh LY;Dávila-Rodríguez J;Rivera-Aponte DE;Zueva LV;Washington AV;Sanabria P;Inyushin MY
通讯作者：
Inyushin MY