Effects of Peripheral APOE on Central Nervous System Functions and AD Pathogenesis

Alzheimer’s disease, as the leading cause of dementia, has become a growing epidemic in our aging society. While aging is the greatest risk factor for AD development, a growing list of genetic and environmental factors also contributes to the risk. Among them, a gene called APOE is the strongest genetic risk factor for AD. The goal of the APOE consortium is to collectively address how a specific gene form called APOE4, which encodes the APOE4 protein, drives up the risk, and how we can target this protein for the development of new therapy. Interestingly, APOE protein is present not just in the brain, but also at a high concentration in the blood, produced primarily by the liver to transport cholesterol and other lipids among different organs. Along with their increased AD risk, individuals carrying the APOE4 gene also are at a greater risk of developing hypercholesterolemia and atherosclerosis compared with those carrying the APOE3 gene. Despite critical knowledge gained in the past two decades in understanding how brain APOE4 regulates AD-related pathologies, we know very little about how peripheral APOE circulating in the blood impacts brain functions and AD-related pathways. Toward this goal, we recently have developed a new set of animal models that allow for expression of APOE only in the liver but not in the brain, thus allowing studies on how liver APOE populated in the blood affects brain functions and AD pathologies. In these animals, we also can turn on or turn off APOE expression during different disease states to address the timing at which APOE4 has the greatest impact. Our hypothesis is that blood APOE4 impairs brain functions and increases AD pathology by injuring blood vessels and by driving up harmful inflammation. This will be pursued through two specific aims:

• In Aim 1, we will compare how blood APOE3 (good form) and APOE4 (bad form) modulate inflammatory responses, blood vessel integrity, and brain functions measured by electrical signals and memory performance.
• In Aim 2, we will address how blood APOE3 and APOE4 affect the clearance of the amyloid component called amyloid beta, the build up of which forms amyloid plaques thought to be the central driver of the AD disease process.

We have established multiple innovative technologies and tools to achieve our goals. This project will include close collaboration with other consortium projects. In particular, the Bu lab has a longstanding collaboration with the Holtzman lab to address how APOE4 drives AD risk. This collaboration will be further strengthened within this APOE consortium using complementary approaches. Collaboration with other consortium projects also will include those with the Wellington team to address vascular effects, the Bateman team to analyze the different forms of APOE in the blood, the Butovsky team to address inflammation, and the Greengard team to study new APOE-related genes and pathways. Our studies will for the first time investigate how blood APOE affects brain functions and AD-related pathways, and how we can develop new AD therapies targeting APOE in the blood.