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Role of Lipid-derived Oligomer Strains in AD Phenotypes

Award Number: R56AG062292
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Role of Lipid-derived Oligomer Strains in AD Phenotypes - ABSTRACT Sporadic Alzheimer disease (sAD) is a neurodegenerative disorder that leads to acute memory and cognition loss in the elderly patients. An important characteristic of sAD is the diverse clinical sub-types that arise from different pathological phenotypes. Determining the molecular underpinnings of such clinical differences is important for diagnostic and therapeutic advances, but has remained a major challenge. Emerging evidence indicates that structural polymorphism within Aß aggregates may cause the observed phenotypes in sAD. However, the relation between the neurotoxic, low molecular weight oligomers of amyloid- ß (Aß) peptides and the observed phenotypes remains unclear. Results from our labs suggest that neurotoxic oligomers of Aß42 formed in the presence of lipids (LDs) faithfully propagate their mesoscopic structure towards morphologically distinct fibrils and selectively induce vascular phenotype in transgenic AD mice. These results suggest that the distinct phenotypes can emerge from specific oligomer conformations, but also raise the question of whether LDs play a key catalytic role in generating distinct oligomer strains that manifest in pathology. We hypothesize that the physiochemical characteristics of LDs modulate Aß aggregation to generate oligomer strains that propagate to elicit discrete phenotypes in the brain. The proposed research will focus on testing this hypothesis by determining the mechanistic understanding of LD-derived oligomer strains with three specific aims: Aim 1 we will focus on understanding the molecular mechanisms that dictate LD- induced oligomer strain generation; Aim 2 will focus on identifying the structures of LD-derived oligomers and how they relate to their propagation propensities, and Aim 3 will focus on determining how LD-oligomers induce phenotypes in mice brains. This project will involve a collaborative effort with biophysical and biochemical aspects investigated in the PI's lab, structural and mechanistic aspects in the Ramamoorthy lab (University of Michigan), molecular modeling work in the Hansmann lab (University of Oklahoma) and animal modeling work in the Levites lab (University of Florida). Together, the proposed research will generate critical insights into how phenotypes emanate from conformations of aggregates in sAD, and open new avenues for potential therapeutic interventions.


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: 2022 ( Subtotal = $2,425 )
2022	2018	UNIVERSITY OF SOUTHERN MISSISSIPPI, THE	2609 W 4TH ST STE H	HATTIESBURG	MS	39401	FORREST	USA	Aging Research	000	1	9/23/2022	NEW	$2,425
														Subtotal = $2,425

Issue Date FY: 2021 ( Subtotal = -$22,650 )
2021	2018	UNIVERSITY OF SOUTHERN MISSISSIPPI, THE	2609 W 4TH ST STE H	HATTIESBURG	MS	39401	FORREST	USA	Aging Research	000	1	4/12/2021	NEW	-$22,650
														Subtotal = -$22,650

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	UNIVERSITY OF SOUTHERN MISSISSIPPI, THE	2609 W 4TH ST STE H	HATTIESBURG	MS	39401	FORREST	USA	Aging Research	000	1	1/7/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $671,162 )
2018	2018	UNIVERSITY OF SOUTHERN MISSISSIPPI, THE	2609 W 4TH ST STE H	HATTIESBURG	MS	39401	FORREST	USA	Aging Research	000	1	9/19/2018	NEW	$671,162
														Subtotal = $671,162

Grand Total All Awards = $650,937

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Role of Lipid-derived Oligomer Strains in AD Phenotypes

Award Number: R56AG062292

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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