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. 2025 Sep:213:107013.
doi: 10.1016/j.nbd.2025.107013. Epub 2025 Jun 30.

Age-related cerebral amyloid angiopathy accumulation in the APPSw mouse model is associated with perivascular inflammation and brain-wide vascular and inflammatory gene and protein changes

Katelynn E Krick  1 , Erica M Weekman  2 , Sherika N Johnson  1 , Tiffany L Sudduth  3 , Colin B Rogers  3 , Emma J Nicolayson  4 , Maureen T Kleinhenz  4 , Donna M Wilcock  5
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Free article

Age-related cerebral amyloid angiopathy accumulation in the APPSw mouse model is associated with perivascular inflammation and brain-wide vascular and inflammatory gene and protein changes

Katelynn E Krick et al. Neurobiol Dis. 2025 Sep.
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Abstract

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.

Keywords: Alzheimer's disease (AD); Cerebral amyloid angiopathy (CAA); Cerebrovasculature; Vascular contributions to cognitive impairment and dementia (VCID).

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:(Donna M Wilcock reports a relationship with Longeveron LLC that includes: consulting or advisory. Donna M Wilcock reports a relationship with Vigil Neuroscience Inc. that includes: consulting or advisory. Donna M Wilcock reports a relationship with SynapsDx that includes: consulting or advisory. Donna M Wilcock reports a relationship with Alzheimer's & Dementia that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.)

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