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Aberrant protein S-nitrosylation mediates Gene-Environment Interactions in AD/ADRD

Award Number: U01AG088679
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Aberrant protein S-nitrosylation mediates Gene-Environment Interactions in AD/ADRD - Project Summary Alzheimer’s disease (AD) and AD-related dementias (ADRD) represent the most common forms of neurodegenerative disease in patients above 65 years of age. Growing evidence has suggested that the potential causes of AD/ADRD in the aging population are multi-faceted and are likely mediated through an interaction of lifestyle, genetic, and environmental risk factors. As an example of environmental factors, air pollution caused by car exhaust and power plant emissions, contains hazardous airborne substances, such as fine particulate matter (PM) with nitric oxide-related species (NOx), and is associated with increased risk of cognitive impairment in AD. However, the molecular mechanisms underlying the interplay of genetic risk factors (such as ApoE4) and environmental air pollution exposures (termed GxE) in AD/ADRD pathogenesis remain largely unknown. In this application, we propose to study the targets of aberrant protein S-nitrosylation after exposure to PM/NOx as found in air pollution in order to better characterize this exposome and to find new potential targets of therapy for AD. In fact, we were the first group to show that increased levels of NO/NOx contribute to synaptic damage, a major correlate to cognitive decline in sporadic AD/ADRD, via aberrant protein S-nitrosylation forming SNO-proteins. For example, our recent findings in human postmortem brains from AD patients vs. age-matched controls of both sexes with multiple genetic backgrounds has produced evidence for aberrantly S-nitrosylated proteins (SNO-proteins) in AD human brain that cause metabolic energetic compromise and resulting synaptic loss in AD, the major neuropathological correlate to cognitive decline. For our proposed work, we will use human induced pluripotent stem cell (hiPSC)-derived 2D cultures and 3D cerebral organoids as well as in vivo xenotransplantation models. In Specific Aims 1 and 2, we will determine the effect of the exposome, represented by PM/NOx present in air pollution, by assessing the S-nitrosoproteome in hiPSC-derived 2D cultures and 3D cerebral organoids as well as in mouse AD models carrying AD-related genetic variants vs. isogenic WT controls after exposure to PM/NOx. In Aim 3, we will identify and validate aberrantly S-nitrosylated proteins formed in response to the PM/NOx exposome as potential therapeutic targets in AD brain using hiPSC-derived 2D cultures and 3D cerebral organoids as well as in vivo mouse xenotransplantation models. We can determine causality of the aberrantly S-nitrosylated proteins by testing non-nitrosylatable mutant forms of the proteins, as we have previously described. Thus, the significance of these S-nitrosoproteomic changes is that they will be linked to cognitive decline in AD, and therefore S-nitrosylated protein changes arising from the exposome may represent potential new therapeutic targets.


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 = $913,756 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	8/10/2026	NON-COMPETING CONTINUATION	$913,756
														Subtotal = $913,756

Issue Date FY: 2025 ( Subtotal = $895,482 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	2	7/22/2025	NON-COMPETING CONTINUATION	$895,482
2025	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	10/22/2024	NEW	$0
														Subtotal = $895,482

Issue Date FY: 2024 ( Subtotal = $913,756 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	9/6/2024	NEW	$913,756
														Subtotal = $913,756

Grand Total All Awards = $2,722,994

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Aberrant protein S-nitrosylation mediates Gene-Environment Interactions in AD/ADRD

Award Number: U01AG088679

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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