Krick Katelynn E, Weekman Erica M, Johnson Sherika N, Sudduth Tiffany L, Rogers Colin B, Nicolayson Emma J, Kleinhenz Maureen T, Wilcock Donna M
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
Neurobiol Dis. 2025 Sep;213:107013. doi: 10.1016/j.nbd.2025.107013. Epub 2025 Jun 30.
Cerebral amyloid angiopathy (CAA) is an extremely common pathology of Alzheimer's disease (AD) included under vascular contributions to cognitive impairment and dementia (VCID). CAA has been reported in 78-98 % of AD cases and has clinical significance when considering side effects that arise when using amyloid targeting immunotherapies. Despite its prevalence, studies addressing CAA mechanisms have been scarce and there are clear gaps in our understanding of how CAA progresses. This study uses Tg2576 mice, who develop CAA over time, to establish a time course of CAA progression at 8-, 14-, and 20-months of age. We identify changes in transcriptomic signatures of glial cells using NanoString nCounter and targeted protein changes using NanoString Digital Spatial Profiling. Meso Scale Discovery and immunohistochemistry are used to establish disease progression. In this study, we saw many changes primarily associated with inflammatory response, with some changes being transient (Tnf, Lsr; VEGF) and others remaining chronically altered (Osmr, Ccl3; CTSD). Overarchingly, many of these changes relate to the perpetuation of inflammation or recruiting additional immune support, which we see across our timepoints. Further, we identified differences in abundance of proteins (CD45, GFAP, CD31) based on presence of CAA positive vessels within a brain region. We also identified sex-specific differences in CAA burden, as well as how glial reactivity and vessel density change during disease progression. This data represents a comprehensive analysis of CAA progression and differential responses to parenchymal and vascular amyloid that could inform future basic and clinical studies.
脑淀粉样血管病（CAA）是阿尔茨海默病（AD）极为常见的一种病理表现，属于血管性认知障碍和痴呆（VCID）范畴。据报道，78% - 98%的AD病例存在CAA，在考虑使用淀粉样蛋白靶向免疫疗法时出现的副作用时，CAA具有临床意义。尽管其普遍存在，但针对CAA机制的研究却很匮乏，我们对CAA如何进展的理解存在明显空白。本研究使用随着时间推移会发生CAA的Tg2576小鼠，来确定8个月、14个月和20个月龄时CAA进展的时间进程。我们使用NanoString nCounter鉴定神经胶质细胞转录组特征的变化，并使用NanoString数字空间分析鉴定靶向蛋白的变化。采用中尺度发现法和免疫组织化学来确定疾病进展情况。在本研究中，我们观察到许多主要与炎症反应相关的变化，一些变化是短暂的（肿瘤坏死因子、Lsr；血管内皮生长因子），而其他变化则持续存在（促红细胞生成素受体、Ccl3；组织蛋白酶D）。总体而言，这些变化中的许多都与炎症的持续或招募额外的免疫支持有关，这在我们所有的时间点都能看到。此外，我们根据脑区内CAA阳性血管的存在情况，鉴定了蛋白质丰度的差异（CD45、胶质纤维酸性蛋白、CD31）。我们还确定了CAA负担的性别差异，以及疾病进展过程中神经胶质反应性和血管密度的变化。这些数据代表了对CAA进展以及对实质和血管淀粉样蛋白的不同反应的全面分析，可为未来的基础和临床研究提供参考。
