Tuesday, July 1, 2025 7/1/2025

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

Award Number: R01AG068992
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $650,726 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	3	4/8/2025	NON-COMPETING CONTINUATION	$650,726
														Subtotal = $650,726

Issue Date FY: 2024 ( Subtotal = $726,954 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	2	5/7/2024	EXTENSION WITH OR WITHOUT FUNDS	$726,954
														Subtotal = $726,954

Grand Total All Awards = $1,377,680

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

Award Number: R01AG068992

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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