Effects of Peripheral ApoE Isoforms on Brain Functions and AD Pathogenesis

Studies show that having apolipoprotein E4 (APOE4) gene and blood vessel diseases (such as hypotension and diabetes) increase a person’s risk for Alzheimer’s disease (AD). Due to the blood-brain barrier (BBB), a protective layer that selectively prevents large molecules in the bloodstream from entering the brain, the apoE produced in the liver and circulated in the bloodstream (periphery) does not mix with apoE produced in the brain. Using a unique inducible mouse model, our studies will for the first time test how peripheral apoE affects brain functions and AD disease progression. Our findings will be very useful in understanding how apoE4 impairs brain health and may ultimately lead to effective treatments for AD.

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly with currently no disease-altering therapy. Having apolipoprotein E4 (APOE4) gene increases a person’s risk of getting late-onset AD. Studies in humans and mice showed that brain amyloid beta (Aβ) levels and amyloid plaque loads are apoE isoform-dependent. ApoE4 impairs glucose metabolism and lipid homeostasis in the brain, and has a reduced ability to control neuroinflammation. Thus, understanding the pathobiology of apoE4 represents a great opportunity both to uncover mechanisms underlying AD risk and also explore a novel target for therapy.

ApoE is highly expressed by the liver and plays critical roles in plasma lipoprotein metabolism. ApoE4 is also associated with a greater risk for hypercholesterolemia and atherosclerosis. As apoE in the bloodstream is separated from that of the brain by the BBB, it is not clear how it affects the function of the central nervous system (CNS) and AD pathogenesis. In Aim 1, we will determine how peripheral apoE3 and apoE4 affect brain health and animal behaviors in our mouse models. In Aim 2, we will examine how peripheral apoE3 and apoE4 affect Aβ metabolism. Using an in vivo microdialysis technique, we will detect Aβ together with multiple large-size molecules in the brains of the free moving animals to understand how these disease-associated molecules affect amyloid deposition and brain functions. Our study will help understand why apoE4 increases the risk for developing AD. Results from this study may provide mechanistic guidelines as to how patients with different APOE isoforms should be effectively treated and facilitate the development of novel therapeutic approaches for AD.