Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE.
Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE.
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DOI：
10.1042/cs20201033
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发表时间：
2021-08-13
期刊：
影响因子：
--
通讯作者：
Roman RJ
中科院分区：
文献类型：
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作者：
Gonzalez-Fernandez E;Liu Y;Auchus AP;Fan F;Roman RJ
细胞外淀粉样蛋白-β和细胞内过度磷酸化的tau蛋白在大脑中的积累是阿尔茨海默病的特征。对阿尔茨海默病发病机制的大部分研究都集中在淀粉样蛋白或tau假说上。这些假说表明，淀粉样蛋白-β或tau聚集是阿尔茨海默病的激发事件，导致下游神经变性、炎症、脑萎缩和认知障碍。已经开发出多种药物，可以有效地防止淀粉样蛋白β或tau蛋白的积聚和/或清除。然而，检查这些治疗剂的临床试验未能显示出预防或减缓疾病进展的效果。因此，在这一领域需要新的视角和对替代治疗靶点的评估。流行病学研究表明，高血压、糖尿病、动脉粥样硬化和中风等心脑血管危险因素与认知功能障碍的发生有显著重叠。这种强烈的相关性使人们重新关注血管对阿尔茨海默病和相关痴呆症的影响。然而，目前还没有发现多少基因和机制。20-HETE是一种有效的血管收缩药，在高血压、脑血流自动调节和血脑屏障完整性方面发挥着复杂的作用。多项人类全基因组关联研究已将产生20-HETE的CYP4A基因突变与高血压和中风联系起来。最近，在人类人口研究中，产生20-HETE的酶的遗传变异也与阿尔茨海默病有关。这篇综述考察了20-HETE在阿尔茨海默病和相关痴呆中的新角色。
The accumulation of extracellular amyloid-β and intracellular hyperphosphorylated tau proteins in the brain are the hallmarks of Alzheimer’s disease. Much of the research into the pathogenesis of Alzheimer’s disease has focused on the amyloid or tau hypothesis. These hypotheses propose that amyloid-β or tau aggregation is the inciting event in Alzheimer’s disease that leads to downstream neurodegeneration, inflammation, brain atrophy, and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of amyloid-β or tau proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to Alzheimer’s disease and related dementias. However, few genes and mechanisms have been identified. 20-HETE is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood-brain barrier integrity. Multiple human genome wide association studies have linked mutations in the CYP4A genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to Alzheimer’s disease in human population studies. This review examines the emerging role of 20-HETE in Alzheimer’s disease and related dementias.