Mutations associated with Alzheimer’s disease and aged serum synergistically elicit blood-brain barrier dysfunction in a tissue-engineered model

BACKGROUND: Alzheimer’s disease is heterogeneous with a wide range of etiological subtypes derived from multiple risk factors. Many of these risk factors are either directly or indirectly related to stresses that act on the blood-bran barrier. Deconvoluting the influence of these stresses on blood-brain barrier function is important in understanding disease mechanisms and subtypes. METHODS: We used a tissue-engineered model with stem-cell derived brain microvascular endothelial cells (iBMECs) to assess the combined influence of cell-intrinsic mutations associated with Alzheimer’s disease (APP(Swe) and PSEN1(M146V)) and the systemic influence of aged blood components by perfusion with aged or young human serum. Blood-brain barrier dysfunction was assessed by transcriptomic analysis of iBMECs, functional measurements, and immunofluorescence imaging. RESULTS: Mutations alone had no impact on permeability of small or large molecular weight solutes. Both aged serum and young serum resulted in increases in permeability of Lucifer yellow and 10 kDa dextran in APP and PSEN microvessels. The combination of aged serum and APP/PSEN1 mutations also resulted in an increase in adhesion of THP-1 neutrophil-like cells, and an increase in sprout length in an angiogenesis assay. CONCLUSIONS: These results suggest that mutations associated with AD harbored by BMECs and age-related changes in plasma protein composition do not individually result in significant BBB dysfunction. However, the combinatorial effect of these stresses can induce modes of BBB dysfunction.