Florijn Barend W, Verwey Niek A, van Etten Ellis S, de Vries Helga E, Wermer Marieke Jh
Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
J Cereb Blood Flow Metab. 2025 Aug 6:271678X251366082. doi: 10.1177/0271678X251366082.
Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease characterized by amyloid-beta (Aβ) accumulation in cortical and leptomeningeal blood vessel walls. Reduced Aβ clearance in the vasculature elevates the risk of CAA, while increasing evidence indicates that enhanced Aβ production in neurons also contributes. The impact of Aβ on the diverse cell types of the neurovascular unit (NVU)-including endothelial cells (ECs), pericytes, neurons, vascular smooth muscle cells (VSMCs), and astrocytes-remains unclear. This narrative review proposes that Aβ accumulation in NVUs during CAA drives a transcriptional response that reduces Aβ clearance while activating a neuron-specific post- transcriptional response that enhances Aβ production. Specifically, Aβ in NVUs was found to initiate a transcriptional cascade that destabilizes endothelial cells, increases blood-brain barrier permeability, and damages pericytes, ultimately inducing inflammatory and dysfunctional changes in VSMCs. These changes cause mitochondrial dysfunction and TGFβ deregulation in neurons, activating profibrotic mechanisms. Post-transcriptional regulation by microRNA networks in neurons affects Aβ processing by controlling the balance between amyloidogenic and non-amyloidogenic pathways through BACE1 and ADAM10 expression respectively. This review improves our understanding of Aβ accumulation in neurovascular units in CAA, potentially leading to better diagnostics, early biomarkers, and tools for prognosis and treatment.
脑淀粉样血管病（CAA）是一种常见的与年龄相关的小血管疾病，其特征是淀粉样β蛋白（Aβ）在皮质和软脑膜血管壁中积聚。血管系统中Aβ清除减少会增加CAA的风险，而越来越多的证据表明神经元中Aβ生成增加也有影响。Aβ对神经血管单元（NVU）的多种细胞类型（包括内皮细胞（ECs）、周细胞、神经元、血管平滑肌细胞（VSMCs）和星形胶质细胞）的影响仍不清楚。这篇叙述性综述提出，CAA期间NVU中Aβ的积聚驱动了一种转录反应，该反应减少了Aβ清除，同时激活了一种增强Aβ生成的神经元特异性转录后反应。具体而言，发现NVU中的Aβ引发了一个转录级联反应，使内皮细胞不稳定，增加血脑屏障通透性，并损害周细胞，最终在VSMCs中诱导炎症和功能失调变化。这些变化导致神经元中的线粒体功能障碍和TGFβ失调，激活促纤维化机制。神经元中微小RNA网络的转录后调控通过分别控制BACE1和ADAM10的表达来调节淀粉样生成途径和非淀粉样生成途径之间的平衡，从而影响Aβ的加工。这篇综述增进了我们对CAA中神经血管单元中Aβ积聚的理解，可能会带来更好的诊断方法、早期生物标志物以及预后和治疗工具。
