Divecha Yasmin Amy, Rampes Sanketh, Tromp Sabine, Boyanova Sevda T, Fleckney Alice, Fidanboylu Mehmet, Thomas Sarah Ann
King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom.
King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom.
Pharmacol Rev. 2025 May;77(3):100052. doi: 10.1016/j.pharmr.2025.100052. Epub 2025 Mar 13.
High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.
稳定的局部微环境促成了高保真神经元信号传导。中枢神经系统屏障实现了对脑微环境的高度稳态调节，并使其与血液中多变且可能具有神经毒性的成分相分离。临床和临床前研究的证据表明，脑微循环、脑灌注不足、血脑屏障功能障碍以及淀粉样蛋白清除减少与阿尔茨海默病的病理生理过程相关。研究这种失调是理解阿尔茨海默病（AD）、确定药物靶点、制定治疗策略以及改善针对这一脆弱人群的处方的关键。本综述分为两部分：第一部分描述脑微循环、脑血流量、细胞外液引流以及神经血管单元的组成部分，重点是血脑屏障；第二部分总结了AD中各个方面是如何改变的。分别讨论神经血管单元结构使我们能够得出结论，即异常的周细胞是理解AD病理生理过程的早期因素且至关重要。周细胞具有多种功能，包括维持血脑屏障完整性、控制毛细血管血流量、毛细血管停滞、神经血管耦合、壁内动脉周围引流、胶质淋巴（glymphatic）引流，进而影响淀粉样蛋白和tau蛋白的清除。周细胞具有血管活性，表达胆碱能和肾上腺素能受体，并表现出载脂蛋白E异构体特异性转运途径。AD中的灌注不足与周细胞介导的反应有关。内皮细胞 - 周细胞（PDGBB - PDGFRβ）信号通路缺陷导致周细胞功能障碍，这促进甚至引发了AD的退变。我们得出结论，周细胞是理解AD病理生理过程的核心，是AD中一个有趣的治疗靶点，并且在再生治疗中发挥着越来越重要的作用。意义声明：神经血管单元和液体循环（包括血液、脑脊液和间质液）的失调和功能障碍在阿尔茨海默病中发生。一个核心因素是异常的周细胞。这对于理解疾病病理生理过程和治疗方法的开发具有根本意义。
