BACKGROUND Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease of the aged and a prominent comorbidity of Alzheimer's disease (AD). CAA can promote a variety of vascular-related pathologies including neuroinflammation, cerebral infarction, and hemorrhages, which can all contribute to vascular cognitive impairment and dementia (VCID). Our understanding of the pathogenesis of CAA remains limited and further investigation of this condition requires better preclinical animal models that more accurately reflect the human disease. Recently, we generated a novel transgenic rat model for CAA (rTg-DI) that develops robust and progressive microvascular CAA, consistent microhemorrhages and behavioral deficits. METHODS In the current study, we investigated perivascular pathological processes that accompany the onset and progressive accumulation of microvascular CAA in this model. Cohorts of rTg-DI rats were aged to 3 months with the onset of CAA and to 12 months with advanced stage disease and then quantitatively analyzed for progression of CAA, perivascular glial activation, inflammatory markers, and perivascular stress. RESULTS The rTg-DI rats developed early-onset and robust accumulation of microvascular amyloid. As the disease progressed, rTg-DI rats exhibited increased numbers of astrocytes and activated microglia which were accompanied by expression of a distinct subset of inflammatory markers, perivascular pericyte degeneration, astrocytic caspase 3 activation, and disruption of neuronal axonal integrity. CONCLUSIONS Taken together, these results demonstrate that rTg-DI rats faithfully mimic numerous aspects of human microvascular CAA and provide new experimental insight into the pathogenesis of neuroinflammation and perivascular stress associated with the onset and progression of this condition, suggesting new potential therapeutic targets for this condition. The rTg-DI rats provide an improved preclinical platform for developing new biomarkers and testing therapeutic strategies for microvascular CAA.

中文翻译：

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rTg-DI 大鼠中强烈的神经炎症和血管周围病理学，这是一种新型的微血管脑淀粉样血管病模型。


背景技术脑淀粉样血管病(CAA)是老年人常见的脑小血管疾病，也是阿尔茨海默病(AD)的重要合并症。 CAA 可促进多种血管相关病变，包括神经炎症、脑梗塞和出血，这些均可导致血管性认知障碍和痴呆 (VCID)。我们对 CAA 发病机制的了解仍然有限，对此病症的进一步研究需要更好的临床前动物模型，以更准确地反映人类疾病。最近，我们建立了一种新型 CAA 转基因大鼠模型 (rTg-DI)，该模型可产生强健且渐进的微血管 CAA、一致的微出血和行为缺陷。方法 在本研究中，我们研究了该模型中伴随微血管 CAA 发生和进行性积累的血管周围病理过程。 rTg-DI 大鼠队列在 CAA 发病时年龄为 3 个月，在疾病晚期为 12 个月，然后定量分析 CAA 的进展、血管周围胶质细胞活化、炎症标志物和血管周围应激。结果 rTg-DI 大鼠出现早发且大量的微血管淀粉样蛋白积累。随着疾病的进展，rTg-DI 大鼠表现出星形胶质细胞和激活的小胶质细胞数量增加，并伴有炎症标记物的独特子集的表达、血管周围周细胞变性、星形细胞 caspase 3 激活和神经元轴突完整性破坏。 结论 总而言之，这些结果表明 rTg-DI 大鼠忠实地模拟了人类微血管 CAA 的许多方面，并为与该病症的发病和进展相关的神经炎症和血管周围应激的发病机制提供了新的实验见解，提示了该病症的新的潜在治疗靶点。健康）状况。 rTg-DI 大鼠为开发新的生物标志物和测试微血管 CAA 的治疗策略提供了一个改进的临床前平台。