# Cell autonomous and non-cell autonomous phenotypes due to genetic risk for late onset Alzheimers disease

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $2,207,391

## Abstract

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.

## Key facts

- **NIH application ID:** 10235199
- **Project number:** 1RF1AG068992-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Wayne W Poon
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,207,391
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235199

## Citation

> US National Institutes of Health, RePORTER application 10235199, Cell autonomous and non-cell autonomous phenotypes due to genetic risk for late onset Alzheimers disease (1RF1AG068992-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10235199. Licensed CC0.

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