Clearance systems in the brain-implications for Alzheimer disease.
Clearance systems in the brain-implications for Alzheimer disease.
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DOI：
10.1038/nrneurol.2015.119
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
de Leon MJ
中科院分区：
文献类型：
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作者：
Tarasoff-Conway JM;Carare RO;Osorio RS;Glodzik L;Butler T;Fieremans E;Axel L;Rusinek H;Nicholson C;Zlokovic BV;Frangione B;Blennow K;Ménard J;Zetterberg H;Wisniewski T;de Leon MJ
毒性蛋白聚集体-淀粉样蛋白-β（Aβ）斑块和过度磷酸化的tau缠结-的积累是阿尔茨海默病（AD）的病理标志。假设Aβ蓄积是由Aβ产生和清除之间的不平衡引起的;事实上，在早期和晚期AD中，Aβ清除似乎都受损。为了制定有效的策略来减缓或阻止AD，了解Aβ如何从大脑中清除至关重要。细胞外Aβ沉积物可以通过各种清除系统从脑中清除，最重要的是通过血脑屏障转运。过去几年的研究结果表明，星形胶质细胞介导的间质液（ISF）整体流动（称为胶质淋巴系统）可能比以前认为的更大部分的细胞外Aβ（eAβ）清除。2015年发现的脑膜淋巴管可能提供另一种清除途径。由于这些清除系统共同作用，将eAβ从大脑中排出，因此其功能的任何改变都可能导致AD。对Aβ清除的理解可能会提供减少过量Aβ沉积和延迟甚至预防疾病发作的策略。在这篇综述中，我们描述了大脑的清除系统，因为它们与AD病理学中涉及的蛋白质有关，主要关注Aβ。
Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.