Toward Developing High-Density Lipoprotein Enriched in Apolipoprotein E as a Potential Biomarker and Therapeutic Targeting Vascular Contributions to Alzheimer’s Disease

2017, 2018, 2020

2020

A major genetic risk factor for sporadic Alzheimer’s disease is a gene called apolipoprotein E (APOE), which codes for the APOE protein. The version of the APOE gene that confers higher AD risk makes the protein APOE4, while the normal version makes APOE3, and the protective version makes APOE2. Exactly how the different versions of this gene/protein contribute to AD is not known. The APOE protein is made both in the brain and outside the brain, but the “brain” and “blood” pools of APOE are separated because APOE does not cross the blood-brain barrier. Importantly, most patients with AD have problems with the blood vessels in their brain, including cerebral amyloid angiopathy (CAA), which is the deposition of amyloid beta—the main component of the hallmark AD plaques—in the brain’s blood vessels. With support from the BrightFocus Foundation, the Weston Brain Institute and Cure Alzheimer’s Fund, we have developed an advanced model of bioengineered human cerebral blood vessels. Using this model, we discovered that circulating high-density lipoprotein (HDL; the “good cholesterol”) on the “blood” side, particularly HDL containing APOE (HDL-E), can help remove amyloid beta that gets stuck in the vessel wall as well as reduce vascular inflammation—two key pathological features of AD. We now seek to understand how the different versions of APOE protein affect this process from both the “blood” and “brain” sides. As astrocytes are the main cell type in the brain that make APOE, we will engineer vessels with astrocytes on the “brain” side that make either APOE2, APOE3 or APOE4 to study how the version of astrocyte APOE affects amyloid beta deposition and vascular inflammation from the “brain” side. We also will isolate HDL-E from healthy people with different versions of the APOE gene to study how circulating HDL-E carrying different versions of the APOE protein affects the same processes from the “blood” side. We then will combine these two approaches to determine whether circulating HDL-E carrying APOE2 or APOE3 on the “blood” side can compensate for the negative effects of APOE4 on the “brain” side. If so, this could open up new ways to treat or prevent vascular components of AD, as HDL-based therapies that can work from the inside of the vessel may not need to enter the brain to be effective. Important new areas of study for the upcoming CureAlz funding period are to establish methods to measure HDL-E in human blood samples, determine whether HDL-E levels are lower in patients with the risk version of APOE and learn whether reduced levels of HDL-E are related to CAA. Developing peripheral treatments that may promote vascular health in the context of AD is especially timely, given that drugs like aducanumab are promising but can have some adverse effects on the cerebral vessels. This new work has the potential to set the stage for safer and/or broader use of new AD drugs expected to hit the market.

2017, 2018

The brain contains approximately 400 miles of specialized blood vessels that protect and nourish it. One important function of these cerebral vessels is to allow amyloid beta, a peptide central to Alzheimer’s disease, to exit the brain. As people age, this function often becomes impaired, and amyloid beta then becomes stuck in the vessels and contributes to other changes that lead to full-blown AD. Risk factors for AD, including genetic (APOE) and lifestyle (exercise, cholesterol) issues, can affect function of cerebral vessels in ways we don’t yet understand. My lab therefore has invented a way to grow human cerebral blood vessels with proper anatomy and function in a test tube. These three-dimensional vessels contain human endothelial cells that form the blood-brain barrier, smooth muscle cells that control blood flow and astrocytes that produce APOE. In this project we will study how APOE affects amyloid beta clearance through and inflammation of cerebral vessels.


Funding to Date

$999,672

Focus

Genes to Therapies™ / Stem Cell Drug Screening

Researchers

Cheryl Wellington, Ph.D.