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Molecular Structural Basis of Non-specific Neuronal Membrane Disruption Induced by Early-Stage Beta-Amyloid Peptide Aggregation

Award Number: R01GM125853
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Molecular Structural Basis of Non-specific Neuronal Membrane Disruption Induced by Early-Stage Beta-Amyloid Peptide Aggregation - Abstract Non-specific disruption of neuronal cell membrane induced by amyloidogenic aggregation of b-amyloid (Ab) peptides is considered a viable mechanism in the pathology of Alzheimer’s disease (AD). Understanding the structural basis of key molecular interactions that are responsible for the membrane disruption remains challenging, mainly due to the heterogeneity nature of Ab-membrane systems and the low abundance of key intermediate states. High-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy provides the most powerful method for studying the membrane-disruptive Ab aggregation in its native-state-mimicking environments, i.e., in model liposomes and/or in the presence of neuronal cells. Our long-term goal is to understand the structural basis of key Ab-membrane interactions that are responsible for the non-specific membrane disruption in neurons. During the last funding period, my group has demonstrated the generality of two distinct membrane-disruptive processes in model liposomes: local membrane leaking induced by on-fibrillation-pathway Ab intermediates and membrane fragmentation induced by off- fibrillation-pathway large Ab oligomers. We have also established ssNMR approaches to investigate the structural features and molecular interactions at the intermediate states of individual processes. These ssNMR measurements allow systematic studies of time-dependent structural changes of Ab aggregates and key Ab-lipid interactions in the time frame of membrane disruption process, as well as the modulations of lipid dynamics due to the Ab amyloidosis. In addition, we are exploring the feasibility for extending the studies from membrane- mimicking liposomes to neuronal cells, by using a multipronged strategy combining in-cell ssNMR spectroscopy with cellular imaging/viability assays/quantitative analysis. The current renewal proposal contains three aims. Aim 1 and 2 seek for finalizing the mechanistic studies of membrane-disruptive Ab interactions in liposomes. Specific mechanistic models are proposed and will be demonstrated using extensive ssNMR experiments, including advanced sensitive-enhancing dynamic nuclear polarization (DNP) ssNMR techniques. Key membrane-interruptive intermediate states (including Ab structural features, lipid dynamics and Ab-lipid interactions) will be elucidated. In Aim 3, we strive to developing in-cell ssNMR approaches and quantitative cellular assays/analysis for probing the molecular basis of Ab-induced cellular membrane disruption. This involves identification of Ab-induced membrane-disruptive intermediate states with neuronal cell lines and establishment of in-cell 31P and DNP-assisted ssNMR spectroscopy, including the optimization of sample conditions and spectroscopic methods. Outcomes from the current period, including both the understanding the membrane disruptive effects and the development of ssNMR-based methods, will pave the way for future studies in primary neurons.


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 = $0 )
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	6	4/8/2025	COMPETING CONTINUATION	$535
2025	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	5	4/8/2025	NON-COMPETING CONTINUATION	-$535
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $336,688 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	002	6	8/20/2024	COMPETING CONTINUATION	$336,688
2024	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	5	12/13/2023	NON-COMPETING CONTINUATION	$0
2024	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	5	8/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,688

Issue Date FY: 2022 ( Subtotal = $276,480 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	5	6/27/2022	NON-COMPETING CONTINUATION	$27,648
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	5	12/22/2021	NON-COMPETING CONTINUATION	$248,832
														Subtotal = $276,480

Issue Date FY: 2021 ( Subtotal = $274,818 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	4	3/1/2021	NON-COMPETING CONTINUATION	$27,482
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	4	12/17/2020	NON-COMPETING CONTINUATION	$247,336
														Subtotal = $274,818

Issue Date FY: 2020 ( Subtotal = $330,777 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	3	12/17/2019	NON-COMPETING CONTINUATION	$246,658
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	002	3	7/20/2020	SUPPLEMENT FOR EXPANSION	$56,712
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	3	3/11/2020	NON-COMPETING CONTINUATION	$27,407
														Subtotal = $330,777

Issue Date FY: 2019 ( Subtotal = $294,466 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	2	12/24/2018	NON-COMPETING CONTINUATION	$247,952
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	2	8/27/2019	SUPPLEMENT FOR EXPANSION	$46,514
														Subtotal = $294,466

Issue Date FY: 2018 ( Subtotal = $254,712 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	1	12/22/2017	NEW	$254,712
														Subtotal = $254,712

Grand Total All Awards = $1,767,941

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Molecular Structural Basis of Non-specific Neuronal Membrane Disruption Induced by Early-Stage Beta-Amyloid Peptide Aggregation

Award Number: R01GM125853

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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