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Aging and hyperglycemia alter molecular mechanisms and hippocampal oscillations consistent with Alzheimer's disease

Award Number: R01AG062762
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Aging and hyperglycemia alter molecular mechanisms and hippocampal oscillations consistent with Alzheimer's disease - Project Summary/Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory. Pathological hallmarks of AD include amyloid-beta (Aβ) plaque deposition, neurofibrillary tangle (NFT) formation and the progressive loss of synapses and neurons. A growing literature has demonstrated immune activation in the brain, in particular activated microglia contribute to the onset and progression of AD by facilitating Aβ deposition and NFTs. There is no known cause for AD, however, several risk factors have been identified in the development of AD, including diabetes mellitus (DM) and advanced age. Patients with DM have a 1.5-4 fold increased risk of developing AD. The precise mechanisms by which DM increases the risk of AD is not known, but DM is associated with immune activation. As DM is more prevalent in aging populations it is likely these 2 risk factors combine in the pathogenesis of AD. We hypothesize that elevated inflammatory activation in DM, that is exacerbated by age is the primary driver of increased risk for AD, given inflammation exacerbates AD pathology. Separate data indicate the endogenous neurotransmitter GABA is capable of modulating activation of microglia and immune function and could serve a therapeutic role in DM patients at risk for AD, as well as AD patients comorbid with DM. In preliminary investigations we have demonstrated administration of an already FDA approved GABA receptor agonist in a DM animal model rescues learning and memory deficits, tau phosphorylation (NFT), and immune activation consistent with AD clinical populations and AD animal model systems. The research proposed will provide an opportunity to determine if the elevated inflammation associated with DM is a major contributor to AD pathology, in both males and females. Further, the experiments proposed will expand on our preliminary data to include evaluation of network function disrupted in AD, as well as determine if the rescue is mediated via direct modulation of microglia. Lastly, the data from the proposed research will elucidate the mechanisms underlying the rescue of AD related pathology and provide the necessary data to support the repurposing of an already FDA approved drug for use in a large subset of the AD population.


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 = -$220,106 )
2024	2021	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	000	2	9/20/2024	NON-COMPETING CONTINUATION	-$220,106
														Subtotal = -$220,106

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	000	2	4/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $793,770 )
2021	2021	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	003	2	7/14/2021	NON-COMPETING CONTINUATION	$657,585
2021	2020	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	002	1	4/15/2021	NEW	$136,185
2021	2020	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	000	1	11/6/2020	NEW	-$603,788
2021	2020	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	001	1	11/11/2020	NEW	$603,788
														Subtotal = $793,770

Issue Date FY: 2020 ( Subtotal = $603,788 )
2020	2020	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Aging Research	000	1	9/14/2020	NEW	$603,788
														Subtotal = $603,788

Grand Total All Awards = $1,177,452

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Aging and hyperglycemia alter molecular mechanisms and hippocampal oscillations consistent with Alzheimer's disease

Award Number: R01AG062762

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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