Hereditary Cerebral Amyloid Angiopathy (HCAA) is a rare inherited form of CAA, characterized by increased vascular deposits of amyloid peptides. HCAA provides a unique opportunity to study the pathogenic mechanisms linked to CAA, as it is associated with severe cerebrovascular pathology. Some of HCAA-associated amyloid-β (Aβ) mutations significantly enhance the interaction between fibrinogen and Aβ, resulting in altered fibrin structure and co-deposition with Aβ in the perivascular space. However, the mechanisms underlying perivascular fibrinogen deposition and the associated cerebrovascular pathology in HCAA remain unclear. To investigate this, we analyzed TgSwDI transgenic mice carrying HCAA-associated mutations and observed a significant age-dependent increase in fibrin(ogen) extravasation and fibrin(ogen)-Aβ colocalization in the perivascular space. Moreover, Caveolin-1, a protein involved in non-specific transcytosis across the endothelium, significantly increased with age in TgSwDI mice and correlated with fibrin(ogen) extravasation. Additionally, we noted significant aquaporin-4 (AQP4) depolarization in the CAA-laden blood vessels of TgSwDI mice, which also correlated with fibrin(ogen) extravasation and fibrin(ogen)-Aβ colocalization. Given that AQP4 plays a crucial role in Aβ clearance via the glymphatic pathway, its depolarization may disrupt this critical clearance mechanism, thereby exacerbating CAA pathology. To further explore the relationship between fibrin(ogen) and these factors, we depleted fibrinogen in TgSwDI mice using siRNA against fibrinogen. This intervention resulted in decreased CAA, reduced caveolin-1 levels, attenuated microglial activation, restored polarized expression of AQP4, and improved spatial memory in fibrinogen-depleted TgSwDI mice. These findings suggest that targeting fibrinogen could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology.
Significance statement: Our study reveals the mechanism by which fibrin(ogen)-Aβ colocalization could exacerbates CAA pathology. Our findings highlight that the age-dependent increase of endothelial caveolin-1 could facilitate fibrin(ogen) extravasation, which binds with Aβ in the perivascular space inducing microglial neuroinflammation and AQP4 depolarization, thus exacerbating CAA pathology. Furthermore, fibrinogen depletion could mitigate CAA severity, reduce microglial activation, restore AQP4 polarization and memory impairment. These results suggest that targeting fibrinogen and caveolin-1-mediated transcytosis may offer new strategies to address CAA-associated cerebrovascular pathology.