APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction

Cerebral amyloid angiopathy (CAA) is closely linked to Alzheimer's disease and is caused by the deposition of amyloid in blood vessels. APOE4 is the primary genetic risk factor for CAA, but the specific cellular source of APOE4 involved in this pathological process is not well understood. In this study, researchers discovered that vascular-associated fibroblasts (VAFs) play a critical role in mediating CAA and associated cerebrovascular dysfunction.

By examining post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, the team found that APOE colocalized with COL6 VAFs near Aβ-laden vessels. To investigate the contribution of APOE4 derived from VAFs in CAA, independent of any parenchymal sources, the researchers utilized 5xFAD mice, in which human APOE4 sequences replace endogenous mouse Apoe coding exons.

This allowed for the selective suppression of APOE4 expression in VAFs through tamoxifen induction of Col1a2-CreERT+. The results showed that APOE4 reduction in VAFs significantly reduced CAA, particularly in leptomeningeal vessels. Moreover, Aβ40, which preferentially associates with vascular amyloid, was notably decreased in the vascular fraction.

VAF APOE4 depletion led to fewer small microbleeds and a 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, while astrocytic reactivity remained unchanged. Functional assessments using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries.

These findings establish vascular-associated fibroblasts as a major compartment-specific driver of CAA and cerebrovascular dysfunction, driven by APOE4.