Abstract Body: Introduction: Cerebral amyloid angiopathy (CAA) leads to amyloid β (Aβ) deposition in the cortical and leptomeningeal vessels, and it is a largely untreatable cause of intracerebral hemorrhage and dementia. Studies estimate a 10-50% prevalence of CAA in the elderly population, positioning CAA as one of the strongest vascular contributors to age-related cognitive impairment. While reduced white matter (WM) volume and altered WM integrity have been reported in CAA, the response of oligodendrocytes – the specialized glial cells responsible for myelin production – to Aβ deposition remains unclear. Further, the potential role of oligodendrocytes in CAA-induced cognitive decline has yet to be elucidated.

Methods: TgSwDI mice harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein were used as a mouse model of CAA. Motor and cognitive behaviors were assessed in male and female C57BL/6 wildtype (WT) and CAA mice at 3 and 12 months of age using the open field test (OFT) and fear conditioning (FC). At 12 months, oligodendrocyte and microglia phenotypes, vascular structure, and Aβ burden were evaluated using flow cytometry and immunostaining.

Results: At 12 months, WT and CAA animals exhibited comparable gross motor activity. CAA mice displayed significant cognitive deficits in FC compared to WT mice, which retained intact cognition (n=6-15/grp, p<0.05). Notably, these cognitive deficits were more prominent in female CAA mice. At 12 months, CAA mice also displayed reduced corpus callosum (CC) thickness. Sex differences were observed in CAA mice in oligodendrocyte (Olig2⁺) numbers in the CC and hippocampal CA1 region (n=4/grp, p<0.05), as well as in microglial (Iba1⁺) phagocytosis of oligodendrocytes (n=7/grp, p<0.01) using immunostaining and 3D reconstruction. Additionally, a higher frequency of disease-associated microglia (DAM, Clec7a⁺) was detected near the CC in CAA mice using flow cytometry and immunostaining (n=4/grp, p<0.01).

Conclusion: CAA mice exhibited cognitive decline without motor impairment, alongside significant changes in oligodendrocyte frequency and increased DAM presence near the corpus callosum. The increase in microglial phagocytosis of oligodendrocytes suggests a potential mechanism underlying oligodendrocyte damage and WM injury in CAA. Further research is needed to clarify whether these changes in oligodendrocytes contribute to cognitive decline in CAA.