Extracellular oligomeric tau (o-tau) and vascular deposition of o-tau has been observed in brains of Alzheimer's disease (AD) patients. In this project, we propose to examine how the direct interactions of o-tau with the basolateral side of human brain microvascular endothelial cells (HBMECs) impact their function, including oxidative stress, inflammation, adhesion molecule expression, membrane tether adhesion, and transendothelial migration of monocytes through activations of NADPH oxidase, cytosolic phospholipase A2 and NF?B. As retina is a part of the brain, we also employ the non-invasive optical coherence tomography (OCT) and OCT angiography (OCTA) (i.e. OCT/OCTA) to study microvascular characteristics and neurodegeneration, as quantified by the ganglion layer thickness (GLT), and their relations to oligomeric amyloid-? (oA?), and o-tau contents in retinas of Tg AD mouse models for studying the influences of human tau and amyloid pathology including APPswe/PSEN1dE9 and 3xTg AD mice. This project will fill the research gap between extracellular o-tau and neurovascular abnormalities in AD by providing information regarding adhesion mechanical responses to o-tau in HBMECs, and changes in retinal vessel network characteristics and GLT in relations to A? and o-tau, and ultimately provide insights into therapeutic strategies for AD treatment by regulating tau's effects.
Both tau and amyloid-? peptide (A?) form unusual clumps in brains of Alzheimer's disease (AD) patients. While A? forms plaques extracellularly, tau has been thought to form tangles within the cytoplasm of neurons. However, increasing evidence shows that tau physiologically exists in the extracellular fluid. In fact, vascular deposition of oligomeric tau (o-tau) was observed in brains of AD patients and Tg2576 mice. In turn, o-tau has been reported to be the most toxic form of tau. These recent findings lead to a new hypothesis that vascular deposition of o-tau is involved in driving the vasculopathy in AD. To test this hypothesis, we examine the roles of NADPH oxidase, cytosolic phospholipase A2, and NF?B in the effects of o-tau on oxidative stress, inflammation, expressions of adhesion molecules, and membrane tether adhesion mechanics in human brain microvascular endothelial cells (HBMECs), and transmigration of THP-1 cells across the HBMEC layer. The retina, as a part of the brain, opens a window for high-resolution study of neurovascular defect. We also employ the non-invasive optical coherence tomography (OCT) and OCT angiography (OCTA) (i.e. OCT/OCTA) to study microvascular characteristics and neurodegeneration, as quantified by the ganglion layer thickness (GLT), and their relations to oligomeric A? (oA?), and o-tau contents in retinas of Tg AD mouse models for studying the influences of human tau and amyloid pathology including APPswe/PSEN1dE9 and 3xTg AD mice. This project will fill the research gap between extracellular o-tau and neurovascular abnormalities in AD by providing information regarding adhesion mechanical responses to o-tau in HBMECs, and changes in retinal vessel network characteristics and GLT in relations to A? and o-tau, and ultimately provide insights into therapeutic strategies for AD treatment by regulating tau's effects.
