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3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability

Award Number: R01AG065549
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability - PROJECT SUMMARY/ABSTRACT This project will expand the acquisition, reconstruction, analysis, and dissemination of 3D electron microscopic (3D EM) reference data, disclosing key ultrastructural details preserved within a remarkable collection of legacy biopsy brain samples from patients suffering from Alzheimer’s Disease (AD). These samples were originally collected, characterized and archived by neuropathologists R.D. Terry and N. Gonatas (at A. Einstein in the 1960’s), with later samples taken as part of a cerebrospinal fluid (CSF) drug infusion study involving S. Mirra (at Emory in the 1980’s). They were re-examined by Ellisman, Masliah, Terry, and Mirra in the 1980s, using early 3D EM methods, and were found to manifest excellent preservation of ultrastructure, showing paired helical filaments (PHF) and amyloid accumulations as well as modifications to subcellular organelles and cytoskeletons of the cell bodies, axonal and dendritic processes. Here, we will exploit recent advances in high throughput, automated 3D EM to massively scale the examination of these precious samples, reconstructing 100s of brain cells with and without PHF, tracking axons (and mapping glia and synapses) through much greater brain volumes than was feasible previously. Our goal is to target areas associated with both plaques and tangles, attending to locations where existing findings suggest cell and network vulnerability and contain molecular interactions suspected by some to underlie the initiation and progression of AD. Supporting investigations into the progression of soma/dendritic degeneration, we will target cells operationally defined to represent a progression of neuronal decline as seen in AD; determining the volume fraction of PHF in the cytoplasm as a practical staging measure and linking this to the characterization of quantitative changes in the microstructure of major subcellular constituents. Likewise, we will analyze the progression of axonal degeneration in and near plaques as data obtained suggests that axons may become dystrophic before their parent cell bodies and their dendrites degenerate.


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 = $748,929 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	5	6/4/2024	NON-COMPETING CONTINUATION	$74,892
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	1/5/2024	NON-COMPETING CONTINUATION	$674,037
														Subtotal = $748,929

Issue Date FY: 2023 ( Subtotal = $748,929 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	1/13/2023	NON-COMPETING CONTINUATION	$748,929
														Subtotal = $748,929

Issue Date FY: 2022 ( Subtotal = $1,064,929 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	3	5/2/2022	NON-COMPETING CONTINUATION	$74,892
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	002	3	8/17/2022	SUPPLEMENT FOR EXPANSION	$316,000
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	2/7/2022	NON-COMPETING CONTINUATION	$674,037
														Subtotal = $1,064,929

Issue Date FY: 2021 ( Subtotal = $747,767 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	2/5/2021	NON-COMPETING CONTINUATION	$747,767
														Subtotal = $747,767

Issue Date FY: 2020 ( Subtotal = $746,606 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	2/27/2020	NEW	$746,606
														Subtotal = $746,606

Grand Total All Awards = $4,057,160

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3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability

Award Number: R01AG065549

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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