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How Distinct are the two Chiral Sulfur Epimers of Amyloid Beta Met35 Sulfoxide in their Aggregation, Toxicity and Reactivity with Methionine Sulfoxide Reductases A and B?

Award Number: R21AG070888
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Amyloid beta (Aß)42 is an aggregation-prone peptide and a believed seminal etiological agent of Alzheimer’s Disease. A common post-translational modification of Aß42 is its oxidation at the methionine (Met) 35 residue. Met35 oxidation is physiologically relevant, with a large portion of Alzheimer’s amyloid plaques made up of Aß42-Met35SO. There is a remarkable level of disagreement in the Alzheimer’s field with regard to both biophysical and biological consequences of Aß42 Met35 oxidation. As such, it has been claimed to both promote and suppress aggregation and it has also been claimed to both enhance and reduce toxicity. Oxidation of Aß42 Met35 renders the sulfur chiral. This means that two and not one Aß42-Met35SO peptides are produced. The interconversion barrier between Aß42-Met35-(R)-SO and Aß42-Met35-(S)-SO is extremely high (we calculated it as 45.2 kcal/mol using quantum chemical methods), and the two peptides have to be considered distinct species under physiological conditions. The formation of two stereochemically stable chiral sulfur epimers in consequence Aß42 Met35 oxidation has never been considered in the Alzheimer’s field. We have recently reported a supercritical CO2-based separation protocol that now allows obtaining Met-(R)- SO and Met-(S)-SO in gram quantities with purities exceeding 99.5%. Using these building blocks, we were able to make the Ab42-Met35-(R)-SO and Ab42-Met35-(S)-SO chiral sulfur epimers with no loss of stereochemical information. Here we propose to determine the degree to which sulfur chirality influences Aß42-Met35-(R)-SO and Aß42-Met35-(S)-SO aggregation, neuronal uptake and toxicity. We also propose to develop assays that use a combination of LC/MS and NMR to measure kinetics of Aß42-Met35-(R)-SO and Aß42-Met35-(S)-SO reduction by methionine sulfoxide reductases (MSR) A and B. Research proposed here is expected to resolve a long-standing controversy with regard to the functional consequences of Aß42 Met35 oxidation and will set the stage for future R01-funded experiments to study toxic actions of Aß42-Met35-(R)-SO and Aß42-Met35-(S)-SO and their reduction to Aß42 through MSRA and MSRB in hippocampal and cortical brain tissue, as well as animal models.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Aging Research	000	2	12/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $183,829 )
2022	2022	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Aging Research	001	2	6/9/2022	NON-COMPETING CONTINUATION	$18,383
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Aging Research	000	2	2/15/2022	NON-COMPETING CONTINUATION	$165,446
														Subtotal = $183,829

Issue Date FY: 2021 ( Subtotal = $222,329 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Aging Research	000	1	2/26/2021	NEW	$222,329
														Subtotal = $222,329

Grand Total All Awards = $406,158

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How Distinct are the two Chiral Sulfur Epimers of Amyloid Beta Met35 Sulfoxide in their Aggregation, Toxicity and Reactivity with Methionine Sulfoxide Reductases A and B?

Award Number: R21AG070888

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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