Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease.
Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease.
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DOI：
10.1007/s00401-020-02215-w
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发表时间：
2020-12
影响因子：
12.7
通讯作者：
Attwell D
中科院分区：
文献类型：
--
作者：
Korte N;Nortley R;Attwell D
针对阿尔茨海默病（AD）晚期事件的治疗，包括淀粉样蛋白聚集（Aβ）和过度磷酸化的tau蛋白，在很大程度上失败了，可能是因为它们是在发生重大神经元损伤后给予的。生物标志物表明，AD最早的事件是脑血流量（CBF）减少。这是由收缩的周细胞引起的毛细血管收缩引起的，可能是由低聚物Aβ引起的。中性粒细胞在毛细血管中的捕获和凝块的形成也会减少CBF，这可能是继发于毛细血管收缩。CBF的下降通过上调产生Aβ的BACE1酶和促进tau过度磷酸化来增强神经退行性变。因此，令人惊讶的是，CBF减少可能通过启动淀粉样蛋白级联本身或由a β产生引起并放大而在驱动认知能力下降中发挥关键作用。在这里，我们回顾了这一领域的发展，这些发展在当前的阿尔茨海默病治疗方法中被忽视，目的是促进新的基于机制的治疗方法。
Therapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aβ and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aβ production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches.
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影响因子：
15.1
作者：
Belarbi K;Cuvelier E;Destée A;Gressier B;Chartier-Harlin MC
通讯作者：
Chartier-Harlin MC
影响因子：
14.8
作者：
Bosco, DA;Fowler, DM;Kelly, JW
通讯作者：
Kelly, JW
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
--
作者：
Brickman, Adam M.;Provenzano, Frank A.;Muraskin, Jordan;Manly, Jennifer J.;Blum, Sonja;Apa, Zoltan;Stern, Yaakov;Brown, Truman R.;Luchsinger, Jose A.;Mayeux, Richard
通讯作者：
Mayeux, Richard
DOI：
10.1115/1.4030824
发表时间：
2015-09-01
影响因子：
1.7
作者：
Akenhead，Michael L.;Horrall，Nolan M.;Shin，Hainsworth Y.
通讯作者：
Shin，Hainsworth Y.