Kaloss Alexandra M, Browning Jack L, Li Jiangtao, Pan Yuhang, Watsen Sachi, Sontheimer Harald, Theus Michelle H, Olsen Michelle L
bioRxiv. 2025 Jun 16:2025.02.05.635937. doi: 10.1101/2025.02.05.635937.
Global reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimer's disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network-a critical supplier of intracortical perfusion-has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD.
Using premortem delivery of Methoxy-XO4 to label Aβ, and arterial vascular labeling, we assessed Aβ burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice.
We show that 12-month-old J20 mice exhibit significant Aβ deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with ∼40% vessel coverage in males and ∼20% in females-substantially exceeding Aβ levels in cortical or hippocampal vessels. This vascular Aβ burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by ∼15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden.
This is the first study to comprehensively characterize meningeal arterial Aβ accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal Aβ pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.
脑血流量（CBF）的全球减少是在阿尔茨海默病（AD）中最早观察到且最为一致的异常之一，早于皮质斑块形成和认知衰退。虽然软膜动脉网络——皮质内灌注的关键供应者——在此背景下一直被忽视，但它可能在早期血管病理学中起关键作用。在此，我们报告了在AD的J20（PDGF-APPSw，Ind）小鼠模型的软膜动脉和小动脉网络中广泛存在的脑淀粉样血管病（CAA）。
使用生前给予甲氧基-XO4标记Aβ以及动脉血管标记，我们评估了老年雄性和雌性野生型（WT）及J20 AD小鼠软膜动脉/小动脉网络上的Aβ负荷和脑血流量。
我们发现12月龄的J20小鼠在主要软脑膜动脉（大脑前动脉、大脑中动脉）和软膜侧支上表现出显著的Aβ沉积，雄性小鼠血管覆盖率约为40%，雌性小鼠约为20%——大大超过皮质或海马血管中的Aβ水平。这种血管Aβ负荷伴随着软膜侧支血管的代偿性扩张和迂曲增加。然而，尽管有这种明显的重塑，J20小鼠的CBF仍降低了约15%，并且这种下降与软脑膜CAA负荷显著相关。
这是第一项全面描述血管性AD临床前模型中脑膜动脉Aβ积累的研究，反映了近期在早期人类疾病中的观察结果。我们的发现表明脑膜CAA是早期CBF破坏的潜在驱动因素，并表明软膜侧支重塑可能反映了对血管功能不全的代偿反应。此外，我们确定了CAA负荷存在明显的性别差异，与人类实质Aβ病理学的性别特异性模式相似。这些结果突出了软脑膜脉管系统作为早期AD病理学中一个新的且研究不足的部位，以及作为保护脑血管完整性的潜在治疗靶点。
