ABSTRACT
APOE genotype is a major genetic risk factor for several neurodegenerative disorders. Compared to APOE3,
APOE4 is associated with greater cognitive dysfunction in older adults, increases Alzheimer's disease risk and
exacerbates progression of vascular dementia, stroke, and traumatic brain injury. Evidence supports a major
role of APOE4 in brain endothelial cell (BEC) dysfunction at the blood-brain barrier in all these conditions. BEC
dysfunction can lead to neuronal dysfunction through disrupting the complex neuronal homeostatic
environment and via entry of proteins and other toxins that can damage neurons directly and via effects on
supporting cells. Due to their unique location, BEC are susceptible to signals from the brain and plasma in
neurodegenerative disorders, which may be particularly relevant for inflammation. Indeed, APOE4,
neuroinflammation, peripheral inflammation and BEC dysfunction are intimately linked to dementia
risk/progression. Our novel in vitro data demonstrate that APOE4-BECs have a unique basal phenotype that
results in disruption of their barrier function with inflammatory stimuli, which we have also found in vivo. Based
on these data our hypothesis is that APOE4-associated BEC dysfunction is a novel therapeutic target for
neurodegenerative disorders. Our goals are to develop our in vitro assays (R61 Phase) and conduct screening
and target identification (ID) (R33 phase) to identify novel compounds that mitigate inflammation-induced
permeability disruption in APOE4-BECs. Our biological rationale is that APOE4 predisposes BECs to
inflammation-induced barrier deficits, thereby increasing the risk/progression of adult-onset
neurodegenerative disorders. The novelty lies in our isolation protocols and assays to target inflammation-
induced increases in paracellular permeability using APOE4-BECs. The clinical relevance is that APOE4 is a
risk factor for neurodegenerative disorders for which there are also in vivo models. Therefore, there are
pathways for the transition of positive hits targeting APOE4-associated BEC dysfunction from preclinical to
clinical studies.