Brain endothelial dysfunction in AD

Abstract

AbstractIncreasing evidence suggests that neurovascular dysfunction and neuro‐inflammation is associated with early stages of Alzheimer’s disease (AD). The neuroprotective blood‐brain barrier (BBB) is indispensable for the maintenance of brain homeostasis and proper neuronal functioning. Dysfunction of the BBB and inflammation thereof significantly contributes to the pathogenesis of AD. Amyloid‐β deposition in the microvasculature of the brain, a process referred to as capillary cerebral amyloid angiopathy (capillary CAA), propagates vascular remodeling, which results in impaired function of the blood‐brain barrier and inflammation thereof. While improving vascular function and dampening neuro‐inflammation may be an attractive new way to fight capillary CAA, the underlying factors that mediate vascular alterations in Alzheimer’s disease and capillary CAA pathogenesis remain largely unknown.Our earlier work indicated that hypoxia is a key mediator of vascular dysfunction, which resulted in the induction of angiopoietin like‐4 (ANGPTL4), a hypoxia‐induced factor, in reactive astrocytes in well characterized post‐mortem tissues of patients with capillary CAA. In vitro studies indicated that ANGPTL4 stimulate endothelial cell migration and sprouting in a 3D spheroid model of human brain endothelial cells. Our more recent work now indicates that bioactive lipids and receptors thereof, like the liver‐X‐receptors, may also affect vascular function. In particular, sphingolipids and ceramides play a crucial role in the neuro‐inflammatory process and was associated with vascular dysfunction. The work on how bioactive lipids affect BBB dysfunction in AD will be discussed during this presentation.