Influence of Extracellular Stiffness on the Blood-Brain Barrier
Bosworth, Allison Michelle
0000-0002-8346-6513
:
2021-07-16
Abstract
Alzheimer’s Disease (AD) is traditionally characterized by the presence of parenchymal plaques comprised of amyloid-β peptide aggregates, but these peptide aggregates can also deposit onto brain vasculature. This condition, called Cerebral Amyloid Angiopathy, occurs in approximately 90% of AD cases and causes a disruption of vessel architecture and increased microhemorrhages. It is unclear if such changes alter the stiffness of the vessel wall, and if stiffness modifications compromise the blood-brain barrier (BBB). Made up of specialized endothelial cells that strictly regulate transport of compounds into the central nervous system, the BBB is critical for maintaining neuronal homeostasis. While peripheral endothelial cells have been shown to have increased permeability in response to substrate stiffness, it is unknown how BBB endothelial cells respond to substrate stiffness cues. This dissertation aims to quantify vessel stiffness in post-mortem human cortical tissue using atomic force microscopy, identifying stiffness changes that occur in AD. Additionally, effects of substrate stiffness on the human BBB were elucidated using an induced pluripotent stem cell-derived in vitro model. The incorporation of hydrogel substrates allowed for delivery of stiffness cues in BBB functional assays and phenotypic analysis. These collective works provide insight into how biophysical changes alter vascular integrity and BBB properties, allowing for the development of more representative disease models.