Garcia Francisco J, Heiman Myriam
The Picower Institute for Learning and Memory, Cambridge, MA, USA.
Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
Mol Neurodegener. 2025 Jan 29;20(1):13. doi: 10.1186/s13024-025-00799-z.
Many diseases and disorders of the nervous system suffer from a lack of adequate therapeutics to halt or slow disease progression, and to this day, no cure exists for any of the fatal neurodegenerative diseases. In part this is due to the incredible diversity of cell types that comprise the brain, knowledge gaps in understanding basic mechanisms of disease, as well as a lack of reliable strategies for delivering new therapeutic modalities to affected areas. With the advent of single cell genomics, it is now possible to interrogate the molecular characteristics of diverse cell populations and their alterations in diseased states. More recently, much attention has been devoted to cell populations that have historically been difficult to profile with bulk single cell technologies. In particular, cell types that comprise the cerebrovasculature have become increasingly better characterized in normal and neurodegenerative disease contexts. In this review, we describe the current understanding of cerebrovasculature structure, function, and cell type diversity and its role in the mechanisms underlying various neurodegenerative diseases. We focus on human and mouse cerebrovasculature studies and discuss both origins and consequences of cerebrovascular dysfunction, emphasizing known cell type-specific vulnerabilities in neuronal and cerebrovascular cell populations. Lastly, we highlight how novel insights into cerebrovascular biology have impacted the development of modern therapeutic approaches and discuss outstanding questions in the field.
许多神经系统疾病和功能紊乱都缺乏足够的治疗方法来阻止或减缓疾病进展，时至今日，任何一种致命的神经退行性疾病都无法治愈。部分原因在于构成大脑的细胞类型极其多样，对疾病基本机制的理解存在知识空白，以及缺乏将新治疗方式输送到受影响区域的可靠策略。随着单细胞基因组学的出现，现在有可能探究不同细胞群体的分子特征及其在疾病状态下的变化。最近，人们对以往难以用批量单细胞技术进行分析的细胞群体给予了更多关注。特别是，构成脑血管系统的细胞类型在正常和神经退行性疾病背景下的特征越来越清晰。在这篇综述中，我们描述了目前对脑血管系统结构、功能和细胞类型多样性的理解，以及其在各种神经退行性疾病潜在机制中的作用。我们重点关注人类和小鼠脑血管系统的研究，并讨论脑血管功能障碍的起源和后果，强调神经元和脑血管细胞群体中已知的细胞类型特异性脆弱性。最后，我们强调脑血管生物学的新见解如何影响现代治疗方法的发展，并讨论该领域悬而未决的问题。
