Caveolin-1 and Aquaporin-4 as Mediators of Fibrinogen-Driven Cerebrovascular Pathology in Hereditary Cerebral Amyloid Angiopathy
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-{beta} (A{beta}) mutations significantly enhance the interaction between fibrinogen and A{beta}, resulting in altered fibrin structure and co-deposition with A{beta} 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)-A{beta} 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)-A{beta} colocalization. Given that AQP4 plays a crucial role in A{beta} 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.