Blood-brain barrier dysfunction in response to Alzheimer's disease mutations and aged serum in a tissue-engineered microvascular model
Alzheimer's disease is a disease of neurodegeneration and aging that affects millions of Americans, and is expected to impact millions more without significant advancement in our understanding of the disease. An emerging focus in Alzheimer's study is the role of the cerebrovasculature in the initiation, progression, and exacerbation of symptomatic disease.  Disruption of the blood-brain barrier, which tightly controls any exchange between systemic circulation and brain tissue, has manifested in post-mortem and in vivo studies of late-stage Alzheimer's disease as microbleeds, dysfunctional glucose transport, and impaired efflux of toxins; additional animal studies have indicated that some vascular dysfunction precedes neuronal degeneration in the progression of the disease.  Thus, to understand the drivers and progression of Alzheimer's disease in hopes of identifying therapeutic breakpoints, the role of blood-brain barrier dysfunction must be investigated. Here, we utilize a tissue-engineered model of the blood-brain barrier with high spatiotemporal resolution to assess its dysfunction with cell-intrinsic mutations associated with Alzheimer's (APP(Swe) and PSEN1(M146V)) and the systemic influence of aged blood components (exposure to aged vs. young human serum). Overall design: total samples collected n = 27; n = 3 for each condition across three cell lines (APP mutant, PSEN1 mutant, WT control) and three serum perfusion conditions (standard media, young human serum supplementation, aged human serum supplementation)