Research Institute of Molecular Medicine and Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia.
Research Center of Neurology, 125367 Moscow, Russia.
Int J Mol Sci. 2021 Apr 28;22(9):4661. doi: 10.3390/ijms22094661.
Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood-brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer's disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer's disease.
慢性神经退行性变的病理生理学主要基于与异常信号转导、兴奋/抑制失衡、兴奋性毒性、突触功能障碍、氧化应激、蛋白毒性和蛋白质错误折叠、局部胰岛素抵抗和代谢功能障碍、细胞过度死亡、神经胶质支持的神经炎症发展以及神经发生失败相关的复杂机制。这些机制与神经血管单元 (NVU) 和血脑屏障 (BBB) 的结构和功能的急剧变化密切相关。NVU 是一组脑细胞（脑微血管内皮细胞 (BMECs)、星形胶质细胞、周细胞、神经元和小胶质细胞），用于调节细胞间相互作用、代谢偶联、局部微循环和神经元兴奋性，以适应大脑的实际需求。被称为 BBB 的 NVU 部分控制内源性和外源性分子进入脑组织的选择性进入以及代谢物向血液的流出，从而提供对有效信号转导和大脑可塑性至关重要的大脑化学平衡的维持。在阿尔茨海默病中，线粒体是淀粉样蛋白诱导的神经退行性变和 NVU 代谢偶联或 BBB 破坏的靶细胞器。在这篇综述中，我们讨论了对线粒体驱动的 NVU 和 BBB 功能障碍的理解，以及如何在当前和未来的 NVU/BBB 体外模型中研究它，以寻找阿尔茨海默病有效药物治疗的新方法。
