Exploring the impacts of APOE genotype switching from apoE4 to apoE2 in the periphery (liver and bloodstream) for AD therapy

Project Summary

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, whereas having APOE2 is protective for AD. Studies showed that brain amyloid beta (Aβ) levels and amyloid plaque loads are apoE isoform-dependent while apoE4 promotes, but apoE2 reduces, the amyloid pathology. In addition, apoE isoforms differentially regulate brain functions, lipid transport, neuronal signaling, cerebrovascular functions, and neuroinflammation with apoE2 (or apoE3) having superior effects than apoE4. The goal of our study is to explore the therapeutic potential of converting harmful apoE4 to protective/neutral apoE2 (or apoE3) in the periphery with a specific focus on reducing the pathogenic effects of APOE4. 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 periphery does not enter the brain. Interestingly, our previous study found that having apoE4 circulating in the bloodstream compromises the vascular heath and impairs brain function. In addition, a recent human clinical trial finding demonstrate that infusion of young plasma has great potential to reverse the neurological impairments associated with aging and AD. Using our unique mouse model in which apoE2 is produced in the liver of apoE4 mice, our studies will for the first time test whether converting apoE4 to protective apoE2 or beneficial/neutral apoE3 in the periphery can restore cognition and brain functions as well as AD-related pathology. We will also examine whether treating apoE4 mice with apoE2 young blood can improve aging-related memory deficits and reduces AD disease progression. In addition, we will explore and identify circulating factors, or novel targets in the brain and bloodstream that are associated with the APOE isoforms and brain function, which may offer clues for more in-depth mechanistic studies. Our study will provide strong preclinical rationale and guidance for designing future human clinical trials by modulating peripheral apoE isoforms, offering novel, individualized therapeutic strategies based on APOE genotype.