A Microphysiological Model for Investigating Aβ-Induced Microvascular Dysfunction and Immunotherapeutic Impact
Description
Anti-amyloid immunotherapies represent a promising avenue for Alzheimer’s disease (AD) treatment by targeting amyloid-beta (Aβ); however, their administration is associated with adverse cerebrovascular effects, including ARIA-E/H (edema/hemorrhage) and Cerebral Amyloid Angiopathy (CAA). Despite growing evidence implicating Aβ in microvascular pathology, the mechanisms governing its impact on the neurovascular unit remain unknown. This study employs a microfluidic-based Familial Alzheimer’s Disease-Brain Microphysiological System (FAD- BMPS) to elucidate Aβ-mediated blood-brain barrier (BBB) disruption, vascular amyloid deposition, and inflammatory cascades. Our findings indicate that Aβ compromises endothelial integrity by destabilizing tight junctions, increasing BBB permeability. While promoting the secretion of tight junction and adhesion proteins. Elevated Aβ concentrations correlate with an upregulation of pro-inflammatory cytokines and chemokines, including, TNF-α, and MMP-9. To further investigate the therapeutic implications, this model will assess the impact of inflammatory function on BBB stability and ARIA-related pathologies. We propose that such interventions modulate endothelial function, exacerbating vascular permeability and inflammatory responses, ultimately contributing to ARIA pathogenesis. The FAD-BMPS offers a platform for dissecting Aβ-induced vascular pathology and evaluating therapeutic interventions, granting mechanistic insights into CAA and ARIA.