Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer’s Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor

• Published in: Journal of Alzheimer's disease 2021-01, Vol.83 (4), p.1651-1663
• Main Authors: Skaaraas, Gry H.E. Syverstad, Melbye, Christoffer, Puchades, Maja A., Leung, Doreen Siu Yi, Jacobsen, Øyvind, Rao, Shreyas B., Ottersen, Ole Petter, Leergaard, Trygve B., Torp, Reidun
• Format: Article
• Language: English
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-210571

Background: Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome. Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and vessel density. Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques. Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density. Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors.