R01AG071682

Reshaping APOE4 and Alzheimer's Brains with APOE2 - Project Summary

The research proposed 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 the introduction of human APOE2 protein into high-risk APOE4 and AD brains positively alters the course of brain aging or disease pathogenesis. This is achieved by bolstering brain resilience through enhanced glycolytic metabolism, which subsequently improves glucose utilization, protein homeostasis, and synaptic activity.

In preparation for this translational endeavor, we have achieved three major milestones critical to its success. Firstly, we have developed a method for the production of physiologically relevant and human-compatible recombinant APOE2 (RHAPOE2) glycoprotein that possesses biological functionality comparable to endogenous human APOE2. Secondly, we have developed a noninvasive approach for brain delivery of RHAPOE2 glycoprotein via modulation of cadherin interactions on the blood-brain barrier (BBB), inducing neuroprotective signaling in APOE4 brains. Lastly, we have developed 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 the 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 the delivery of RHAPOE2 glycoprotein. This regimen should result in the deposition of RHAPOE2 throughout cortical and hippocampal regions, upregulation of brain glycolytic metabolism, and avoidance of 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 expressing physiological levels of human APOE3 or APOE4 and human wild-type APP proteins. The third aim will be investigated in humanized mouse models expressing physiological levels of human APOE3 or APOE4 and human mutant APP proteins. This aim aims 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 an RHAPOE2-based protein therapy can potentially be developed into an effective and safe intervention for AD.

University Of Kansas Center For Research

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Lawrence, Kansas 660457552 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 478% from $580,933 to $3,356,041.