Replacement of Peripheral APOE4 with APOE2: Effects on AD Pathogenesis.

Abstract The current proposal is designed to augment and expand upon our currently funded AD Strategic Fund ABA project titled “APOE Allelic Switching to Delay or Prevent Alzheimer''s Disease”. The parent award leverages our novel APOE ‘switch’ mouse model (4s2), which employs the Cre-LoxP system to allow for temporal and cell/organ selective allele switching from E4 to E2, to study the effects of microglia-specific APOE replacement. Although the vast majority of AD research has focused on the brain-derived pool of ApoE (as does the parent award), exciting recent studies strongly suggest that the liver-derived pool of ApoE is a significant contributor to key AD pathologies such as amyloid accumulation and breakdown of the blood brain barrier (BBB). However, these studies did not address the potential neuroprotective role of ApoE2, nor did they determine whether the peripheral pool of ApoE can protect from AD pathology in the presence of CNS ApoE4 (as is the case in at risk human populations). The aims proposed in this project will reveal for the first time if hepatocyte- and/or vascular-derived ApoE2 is sufficient to mitigate AD pathology even in the presence of cerebral ApoE4. These highly translational questions will be addressed by testing how a ‘switch’ in APOE4 to APOE2 expression in vivo affects cerebral i) transcriptomic and metabolomic signatures, ii) BBB integrity, iii) amyloid deposition, and iv) cognitive function. These output measures will be defined in two primary peripheral sources of ApoE, hepatocytes (Aim 1) and vascular endothelial cells (Aim 2). These experiments are designed to run in parallel with the currently funded Alzheimer’s Association work and will be completed within the original timeframe of the parent award (in this case, 10/01/22 – 09/30/25. The proposal is supported by preliminary data that demonstrates clear feasibility of targeting these specific peripheral pools of ApoE using our novel 4s2 mouse strain. The proposed output measures are all based on well-tested in-house workflows within the Johnson (PI) and Morganti (Co-I) labs that are currently being employed for the parent award. Finally, relative to strategies that target brain-derived ApoE, peripheral-specific strategies are less invasive and thus represent a highly translatable and potentially impactful approach.