Friday, May 16, 2025
5/16/2025
Cell autonomous and non-cell autonomous phenotypes due to genetic risk for late onset Alzheimers disease - Recent AD GWAS studies have uncovered a number of risk single nucleotide polymorphisms (SNPs) within genes predominantly expressed or upregulated in microglia in association with pathology suggesting that altered microglia function plays a critical role in disease etiology. Each of these polymorphisms can either confer increased or decreased risk and it will be important to understand how inheritance of each of these polymorphisms impact microglia function to modify disease risk. One identified AD GWAS risk SNP rs3865444 is near the CD33 gene, confers protection from AD, and is found in linkage disequilibrium with rs12459419 SNP, which leads to skipping of exon 2 that encodes the sialic acid-binding domain. CD33 is a member of the Sialic acid-binding immunoglobulin-like lectin (Siglecs) family of receptors in which sialic acid binding transmit signals from the extracellular microglial environment leading to downstream microglia signaling and a subsequent microglia cellular response/change. Because CD33 lacks a true murine ortholog, the study of CD33 requires human cells. The ability to generate microglia-like cells (iMGLs) from iPSC and development of microglia functional assays in my lab will enable investigation of the role of exon 2 skipping on microglia function. Patient and CD33 isogenic induced pluripotent stem cells (iPSCs) will be used to derive iMGLs to interrogate microglia function in the context of differing CD33 genotype. Using liposomal nanoparticles that bring together ligands of two receptors, we will examine the role of CD33 as a co-receptor in modulating Dap12 and FcRg signaling. In addition, we will investigate the functional significance of an interferon microglia signature uncovered by whole transcriptome analysis of patient-derived microglia-like cells. Lastly, a novel AD mouse model facilitating xenotransplantation will be employed to examine the CD33-D2 interferon signature in vivo and whether it improves behavior, reduces AD pathology, and therefore can be targeted as a novel AD therapeutic.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).