PROJECT SUMMARY
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.
