Alzheimer?s Disease (AD) is a neurodegenerative disorder characterized by misfolded, aggregated proteins (in particular, amyloid beta and tau) and chronic activation of the brain?s innate immune system, especially microglia, or brain-resident macrophages, which modulate neurodegeneration. Microglia activation and neurodegeneration may be regulated by apolipoprotein E (apoE), with murine studies demonstrating that apoE deletion prevents microglia from acquiring a neurodegenerative phenotype that was required for neuronal cell death. Other murine studies have shown that microglial depletion by pexidartinib (PLX, a selective CSF1R/c- kit/FLT3 inhibitor that has been shown to readily cross the blood brain barrier and eliminate microglia), can block neurodegeneration and tauopathy in an apoE4 murine model of accelerated neurodegeneration. Microglia may also be affected by allogeneic hematopoietic stem cell transplantation (HCT). While HCT is predominantly performed to treat malignant and nonmalignant conditions of the hematopoietic and lymphatic systems, pre-HCT chemotherapy and radiation to remove the donor hematopoietic system and allow engraftment of the recipient hematopoietic system also has the indirect effect of inducing replacement of recipient microglia with donor microglia-like cells. Therefore, one could theorize that an APOE4 carrier, which represents the strongest genetic risk factor for late-onset AD, may benefit from replacement of diseased microglia with microglia-like cells from a healthy donor (i.e. APOE2 homozygote) through the combination of HCT and PLX (HCT+PLX). Unlike HCT alone, which could take 6 months for full effect, HCT+PLX may achieve microglial turnover in a matter of weeks. And unlike PLX alone, HCT+PLX has the advantages of short-term use of PLX (thus avoiding prolonged toxicities such as cytopenias or liver injury), reconstitution with healthy donor microglia-like cells (vs. suppression), and a potentially permanent treatment response (?cure?). We propose to test the hypothesis that HCT+PLX results in complete microglia turnover and prevention of neurodegeneration and tauopathy in a transgenic tau/apoE4 murine model developed by co-I Sullivan. The P301S Tau/APOE4/4 (TE4) mice exhibit dramatic cortical atrophy between 6-10 months of age and will serve as the recipients of HCT. Human apoE2 or apoE4 knock in mice will serve as donors. Endpoints include behavioral studies, Tau protein levels, and degree of microglial turnover. Positive results will lay the groundwork for translation of this novel approach to clinical trials of HCT+PLX in humans.

Public Health Relevance

Hematopoietic stem cell transplantation (HCT) combined with the drug pexidartinib (PLX) is an innovative strategy to replace diseased microglia, a type of immune cell in the brain that contributes to the development of Alzheimer?s Disease, with healthy microglia-like cells derived from the HCT donor. Given the excellent outcomes with HCT for non-cancerous conditions (including neurological conditions), and that pexidartinib is approved by the Food and Drug Administration for human use, the success of this preclinical proposal could pave the way for human translation of HCT+PLX for the prevention and treatment of AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Martin, Zane
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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