Tuesday, December 16, 2025 12/16/2025

Microglial heparan sulfate in the modulation of APOE function and neurodegeneration

Award Number: R01AG072468
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Microglial heparan sulfate in the modulation of APOE function and neurodegeneration - Heparan sulfate (HS), a sulfated glycan expressed at the cell surface and in extracellular matrix, has long attracted attention as a putative factor involved in Alzheimer's disease (AD), based on circumstantial evidence from in vitro and clinicopathological studies. Nevertheless, the functional significance of HS in AD, especially in the late-onset type (LOAD) that comprises more than 90% of AD cases, is elusive. Recent human genomic studies implicate ApoE and microglia as dominant contributors to neurodegeneration in LOAD. The APOE gene is the strongest known genetic risk factor for LOAD. Accumulating data indicate that ApoE proteins exert immunomodulatory effects on microglia, and that this function of ApoE is at least partly mediated by the TREM2 receptor, another AD risk factor that is expressed by microglia. Among the three human APOE alleles, the APOE4 allele confers an increased risk for LOAD, while the APOE2 allele confers a decreased risk relative to the more common APOE3 allele. The molecular basis of these allele- specific risk variations is one of the key unanswered issues in AD research. In this context, it is interesting to note that ApoE proteins bind HS in an isoform-specific manner — ApoE4 exhibits 2- to 3-fold greater affinity for HS than ApoE2 and ApoE3, thus apparently correlating with their relative AD risks. Furthermore, a recent report regarding the unique case of a Columbian woman, who carries a highly detrimental PSEN1E280A mutation, suggests that her APOE3 Christchurch mutation, which abolishes the affinity of ApoE3 for HS, confers strong protection against neurodegeneration and cognitive impairment. Also suggesting the functional involvement of HS in LOAD are recurrent reports of genetic association of HS sulfotransferase genes with LOAD. In a series of preliminary studies, we have obtained multiple pieces of evidence suggesting that the strong interaction of HS with ApoE4, relative to its interactions with ApoE2 and ApoE3, is the key underlying mechanism by which ApoE4 exerts a detrimental effect on the brain. Significantly, we have found that haploinsufficient reduction in HS expression leads to the mitigation of synapse loss and microglial activation in the PS19 TauP310S mouse model. We hypothesize that HS plays a critical role in mediating the ApoE4 effect on microglial response and function, and that the detrimental effect of the APOE4 allele is mainly due to its stronger interaction with the 3-O sulfate-rich HS species expressed in microglia. We will: (1) determine the role of HS in ApoE-TREM2 interaction and signaling in microglia; (2) determine the role of microglial HS in ApoE/ABCA1-mediated cholesterol efflux; and (3) examine in vivo effects of microglial HS on brain pathology and function in AD mouse models. This research will provide entirely novel insights into the role of HS in microglia, and moreover, into long-term questions regarding the isoform-specific risk of APOE variants. Successful completion of this project will reveal the ApoE4-HS interaction as a promising therapeutic target for reducing AD risk in APOE4 carriers.


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: 2026 ( Subtotal = $522,864 )
2026	2026	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	12/10/2025	NON-COMPETING CONTINUATION	$522,864
														Subtotal = $522,864

Issue Date FY: 2025 ( Subtotal = $569,341 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	11/22/2024	NON-COMPETING CONTINUATION	$522,864
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	4	8/4/2025	NON-COMPETING CONTINUATION	$46,477
														Subtotal = $569,341

Issue Date FY: 2024 ( Subtotal = $580,960 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	3	5/1/2024	NON-COMPETING CONTINUATION	$58,096
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	11/29/2023	NON-COMPETING CONTINUATION	$522,864
														Subtotal = $580,960

Issue Date FY: 2023 ( Subtotal = $580,960 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	1/5/2023	NON-COMPETING CONTINUATION	$580,960
														Subtotal = $580,960

Issue Date FY: 2022 ( Subtotal = $580,960 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	1/25/2022	NEW	$580,960
														Subtotal = $580,960

Grand Total All Awards = $2,835,085

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Microglial heparan sulfate in the modulation of APOE function and neurodegeneration

Award Number: R01AG072468

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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