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Purification and Characterization of a toxic AD associated intracellularly generated amyloid beta fragment

Award Number: R21AG079095
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Purification and Characterization of a toxic AD associated intracellularly generated amyloid beta fragment - ABSTRACT There are over 5 million cases of Alzheimer’s disease (AD) in the US, the number of cases is expected to nearly double over the next 15 years, and the total annual economic costs are over $225 billion. Despite this, there is still no effective treatment for AD. The protein amyloid-beta has long been linked to AD, but much confusion over the role of amyloid-beta in AD still exists and therapeutics targeting amyloid-beta have had limited success. Amyloid plaques are hallmark features of AD, but plaque loads do not correlate well with AD progression, and studies suggest that oligomeric amyloid-beta forms rather than fibrillar forms are the relevant neurotoxic species in AD. In vivo, amyloid-beta is a very heterogeneous protein, and many distinct monomeric and aggregated variants are present in human AD brain. Since protein conformation is directly related to function, determining the conformations of key Aβ variants is crucial to understanding their mechanistic roles in AD. However, the 3- D structures of relevant oligomeric amyloid-beta variants involved in AD neurodegeneration remain elusive. This is likely due to the fact that the different oligomeric amyloid-beta variants are present at only very low levels in human AD samples making structural analysis difficult. The proposed research is focused directly on this problem: here we will generate and characterize a key oligomeric amyloid-beta aggregates found in human AD brain but not cognitively normal brain tissue using antibody derived tools (Fabs) generated in our lab. The C6T Fab selectively recognizes a key intracellularly generated oligomeric aggregates of amyloid-beta that is present in AD brain tissue but not tissue from cognitively normal age-matched control brain tissue. The C6T Fab will serve as the foundation of the proposed research, which seeks to enable the complete structural and biochemical characterization of the toxic oligomeric forms of amyloid-beta found in AD brain tissue. The C6T Fab will be used to isolate the toxic intracellularly generated amyloid-beta variant via immunoprecipitation. Mass spectrometry will then be used to determine the protein composition of the generated aggregates. Since the aggregates generated from human brain tissue may be quite heterogeneous due to the extensive post-translational modifications of amyloid-beta in human brain, we will also similarly isolate and characterize the toxic cell generated amyloid-beta aggregate as generated in the mammalian cell line, 7PA2. These studies will provide the framework for further 3-D characterization studies of this key amyloid-beta variant. We have assembled a team with unique capabilities in Fab development, 3-D structure determination and protein modeling to perform these studies. Structural information of the different oligomeric amyloid-beta species will be vitally important to our understanding of how they interact with different cellular targets and to help devise appropriate therapeutic strategies. These methods could be easily applied to other key protein variants implicated in neurodegenerative diseases including tau, alpha-synuclein and TDP-43.


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 = -$482 )
2026	2022	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Aging Research	000	1	1/8/2026	NEW	-$482
														Subtotal = -$482

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	5/16/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $431,750 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	7/28/2022	NEW	$431,750
														Subtotal = $431,750

Grand Total All Awards = $431,268

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Purification and Characterization of a toxic AD associated intracellularly generated amyloid beta fragment

Award Number: R21AG079095

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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