Grant: Project Grant - PA: Neurosciences, Mental Health and Addiction

Genetic variants in apolipoprotein E (apoE) account for most of the risk of Alzheimer's Disease (AD). Humans have three genetic types of apoE, called apoE2 (the protective form), apoE3 (the neutral form), and apoE4 (the risky form). Exactly how apoE affects AD is not known. ApoE is made by multiple cell types in the brain, including astrocytes. Although apoE is also made by the liver, peripheral apoE has largely been ignored in AD as apoE does cross the blood brain barrier. As most AD patients have cerebrovascular pathologies including cerebral amyloid angiopathy (CAA), we hypothesize that brain and peripheral apoE may interact at the cerebral vessel. We recently pioneered a novel experimental platform to investigate vascular contributions to AD, where we engineered three-dimensional human blood vessels with both a "brain" side and a "blood side". We showed that addition of Abeta to the "brain side" increased CAA, especially in the presence of apoE4. We also showed that addition of high-density lipoprotein (HDL; good cholesterol) to the "blood side" prevented CAA, even in the presence of "brain" apoE4. Further, we recently found that HDL particles enriched in apoE (HDL-E) are best at preventing CAA. We now propose to use our innovative model to determine the relative contributions of astrocyte apoE and HDL-E on CAA, Abeta transport and monocyte binding in bioengineered vessels. We will first engineer vessels with astrocytes that express apoE2, apoE3 or apoE4 to study how astrocyte apoE genotype affects CAA from the "brain" side. We will then isolate HDL-E from healthy people of different apoE genotypes to study how circulating HDL-E affects CAA from the "blood" side. We will then combine these approaches to test whether HDL-E from apoE3 donors can counteract astrocyte apoE4. If so, this could open up new ways to treat or prevent vascular AD risk factors, as therapies that can work from the inside of the vessel may not need to enter the brain to be effective.