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Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy

Award Number: R01AG073434
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy - PROJECT SUMMARY In Alzheimer's disease (AD) research, much focus has been on oligomeric assemblies of the amyloid-β (Aβ) peptide (a small protein). Oligomers are small nanoparticles produced by the aggregation of 50 or fewer peptide molecules. Peptide aggregation most readily produces amyloid fibrils, and it is a mystery what prevents some oligomers from aggregating further into fibrils. Even within oligomeric and fibrillar aggregate classes, peptide aggregates with a range of structures have been detected. Nevertheless, structural biology methods require stable and structurally homogeneous samples to achieve high-resolution information. To elucidate what oligomer structures are possible and which of these structures should be targeted by AD therapies, experiments are designed to understand Aβ assembly in general terms. Preliminary data show that it is possible to produce stable homogeneous samples of a 150 Aβ oligomer (32 Aβ peptide molecules) and study its structure using solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM). Notably, the 150 kDa oligomer structure is unlike any previously understood Aβ assembly, and this observation presents a unique opportunity to probe how oligomer and fibril structures may differ. The project will pursue high-resolution atomic-level characterization of the 150 kDa oligomer by integrating solid-state NMR, cryo-EM, and computational modeling. The work further seeks to generalize understanding of Aβ assembly mechanisms by testing hypothesized assembly pathways inspired by the 150 kDa oligomer. The proposed work will: achieve a 3-dimensional image of the 150 kDa oligomer using cryo-EM (Aim 1); measure complementary atomic-level structural constraints with solid-state NMR (Aim 2); and test mechanistic hypotheses to produce new oligomers compatible with EM and NMR workflows (Aim 3). Knowledge of what oligomer structures are possible for Aβ (and how to isolate specific structures) is critical for developing new Alzheimer's therapeutics, implementing strategies for early detection, and designing mechanistic studies in disease 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: 2025 ( Subtotal = $440,852 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Aging Research	000	2	5/1/2025	EXTENSION WITH OR WITHOUT FUNDS	$440,852
														Subtotal = $440,852

Grand Total All Awards = $440,852

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Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy

Award Number: R01AG073434

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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