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Metformin and Alzheimer's disease: Underlying Mechanisms that Ameliorate Progression

Award Number: R56AG069676
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: 08/31/2022

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Metformin and Alzheimer's disease: Underlying Mechanisms that Ameliorate Progression - Summary Aging is a major risk factor for Alzheimer’s disease (AD). Progression of AD has been linked with 1) an abnormally high systemic and mucosal inflammation in elderly organs, including the brain; 2) dysfunctional permeability (leakiness) in gut and blood-brain barriers (BBB); 3) suppressed autonomic (vagus) nerve activity linked with increased inflammation; and 4) increased amyloid beta (Aβ) and Tau accumulation. However, no currently available drugs target aging-related gut and BBB leakiness and/or vagus nerve suppression, to reduce inflammation. Intriguingly, metformin (a safe and clinically approved drug commonly used to treat diabetes) reduces gut and BBB leakiness and consequent inflammation to attenuate AD. This research proposal is designed to identify the mechanisms by which metformin reduces gut and BBB leakiness and/or vagus nerve function to halt inflammation and AD progression. Our preliminary studies in older mice established that metformin decreased gut leakiness and inflammation and modulated gut microbiota toward increased production of butyrate, a beneficial microbial metabolite and indicator of healthy microbiota. Metformin also improved cognitive function and reduced inflammation and AD markers in the brains of older and AD transgenic (APP/PS1) mice. These results demonstrate that metformin modulates gut-brain axis and reduces AD progression, but how metformin causes these changes is not known. We hypothesize that metformin beneficially modulates gut microbiota to suppress gut leakiness and inflammation and reduce AD progression. Mechanistically, we hypothesize that metformin-mediated suppression of inflammation in gut are mediated by (i) stimulating vagus nerve in the gut and/or (ii) reducing BBB leakiness, which reduces brain inflammation and AD progression. Three Specific Aims test this hypothesis. In Aim 1, to determine whether metformin-modified gut microbiota is causal for its effects to ameliorate AD, we will transplant fecal microbiota from metformin-treated and control AD mice into gut-cleansed APP/PS1 mice (murine model of AD), and assess markers of gut and brain inflammation, gut permeability, and AD progression. In Aim 2, we will assess whether metformin-induced changes in gut involves (i) vagus nerve and/or (ii) BBB permeability to reduce brain inflammation and AD progression. In Aim 3, we will assess whether metformin can delay or treat the pathology of AD by treating adults and older APP/PS1 mice with metformin as AD progresses. Outcomes will establish proof-of-concept and provide the critical preclinical data to support metformin as a therapy to prevent AD progression. Led by an NIH-trained new investigator, in concert with multidisciplinary experts in cutting-edge technologies, this study is timely in addressing the RFA- AG-20-044 (The Biological Mechanisms of Metformin Effects on Aging and Longevity- R01, Clinical Trial Not Allowed). With this study, we will establish the biological mechanism(s) by which metformin can be a potential new therapy for aging-related AD, a debilitating public health problem in older adults.


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: 2023 ( Subtotal = -$634 )
2023	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	8/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$634
2023	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	001	2	8/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$634

Issue Date FY: 2022 ( Subtotal = -$1,227 )
2022	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	001	2	1/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$294,450
2022	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	003	2	3/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$605
2022	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	1	1/7/2022	NEW	-$294,450
2022	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	004	1	6/29/2022	NEW	-$1,227
2022	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	002	1	3/16/2022	NEW	-$605
														Subtotal = -$1,227

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	1	9/15/2020	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $385,639

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Metformin and Alzheimer's disease: Underlying Mechanisms that Ameliorate Progression

Award Number: R56AG069676

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: 08/31/2022

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