Reshaping ApoE4 and Alzheimer's Brains with ApoE2

PROJECT SUMMARY The research we propose in this application seeks to translate our recent understanding of the neuroprotective mechanism associated with the human apolipoprotein E2 (ApoE2) genotype into a therapeutic opportunity to prevent and treat Alzheimer's disease (AD). The overarching hypotheses are that introduction of human ApoE2 protein into high-risk ApoE4 and AD brains positively alters the course of brain aging or disease pathogenesis by bolstering brain resilience through enhanced glycolytic metabolism, which subsequently improves glucose utilization, protein homeostasis, and synaptic activity. In preparation, we have achieved three major milestones critical to the success of this translational endeavor: (1) development of a method for the production of physiologically relevant and human-compatible recombinant ApoE2 (rhApoE2) glycoprotein that possesses biological functionality comparable to endogenous human ApoE2; (2) development of a noninvasive approach for brain delivery of rhApoE2 glycoprotein via modulation of cadherin interactions on the blood-brain barrier (BBB), which induces neuroprotective signaling in ApoE4 brains; and (3) development of novel humanized knock-in mouse models that respectively target human sporadic (sAD) and familial AD (fAD), which are expected to provide high predictive validity for translating bench successes to bedside. The proposed studies will pursue three specific aims. Building on our initial success, the objective of the first aim is to determine the therapeutically optimal regimen for delivery of rhApoE2 glycoprotein that will result in deposition of rhApoE2 throughout cortical and hippocampal regions and upregulation of brain glycolytic metabolism without eliciting adverse reactions. The objective of the second aim is to evaluate the therapeutic impact of rhApoE2 delivery, in combination with age and sex, on brain changes associated with sAD in humanized mouse models that express physiological levels of human ApoE3 or ApoE4 and human wild-type APP proteins. The third aim will be investigated in humanized mouse models that express physiological levels of human ApoE3 or ApoE4 and human mutant APP proteins to evaluate the therapeutic impact of rhApoE2 delivery on brain changes associated with fAD, and how the rhApoE2-mediated effects are modified by a combination of age, sex, ApoE genotype, and disease status. Our overall goals for the proposed research are to establish the plausibility of targeting brain metabolic resilience as a disease-modifying strategy and generate proof of concept as to whether a rhApoE2-based protein therapy can potentially be developed into an effective and safe intervention for AD.