High-Density Lipoprotein in Alzheimer's Disease

Over the funding period we aim to mechanistically characterize how high-density lipoprotein, a blood lipid transporter modulates cerebrovascular health in the context of Alzheimer’s disease. We previously showed that HDL promotes brain vessel health in Alzheimer’s disease. In particular we found that HDL containing apolipoprotein E (apoE) are the most active. However HDL is circulating in the blood and to promote vessel health it must interact with the vessel wall, a process that remains poorly understood. Here we will measure how HDL interacts with the different cells composing the brain vessels. In addition, because apoE is the major genetic risk factor for Alzheimer’s disease, we will analyze how apoE genotypes influence HDL interaction with brain vessel cells.

The role of the brain’s blood vessels in Alzheimer’s disease is well recognized, as they help to clear the build up of cerebral waste and cardiovascular diseases’ risk factors such as diabetes, hypertension and dyslipidemia are associated with increased risk of Alzheimer’s disease. However, how blood-circulating factors exactly affect brain vessel and neuron health remains poorly understood mainly due to the lack of adequate experimental system with which to study how the human brain and blood interact. Using a human blood vessel grown in the test tube, we aim here to uncover how blood lipid transporter namely high-density lipoprotein (HDL, the good cholesterol) promotes brain vessel health.

Our proposal builds upon human based bioengineered brain vessels cultured in the test tube that retain both functional and anatomical properties of native vessels. Because each component of these vessels are modifiable and human blood-lipid carried can be circulating through these vessels, they offer a unique approach to mechanistically study biological and pathological questions in a human relevant system.

Our proposal will help to better understand the role of blood circulating lipid carriers in Alzheimer’s disease ultimately helping to the development of lipoprotein based or targeted therapeutics.