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Modulation of the liver-brain axis by alcohol and its impact on Alzheimers disease pathology

Award Number: R01AG072896
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Modulation of the liver-brain axis by alcohol and its impact on Alzheimers disease pathology - PROJECT SUMMARY The long-term goal of this proposal is to determine how chronic alcohol intake modulates the liver-to-brain axis to induce and/or promote Alzheimer's disease (AD) pathology. Studies have largely focused on the direct action of alcohol on the brain and studies looking outside the brain to understand how alcohol modulates AD pathology are lacking. Our exciting preliminary data have identified two potential alcohol-induced changes to the liver that could induce and/or promote AD pathology in the brain. First, we have discovered that chronic alcohol feeding reduces hepatic low-density lipoprotein receptor-1 (LRP1), a receptor essential in removing peripheral amyloid-beta (Aβ). Since peripheral Aβ can be transported across the blood-brain barrier (BBB) by receptor for advanced glycation end products (RAGE) and become deposited in the brain, it is conceivable that altered LRP1- mediated hepatic Aβ clearance can significantly affect brain Aβ load. Second, our work shows that peripheral tumor necrosis factor-α (TNF-α) secreted by the liver and other organs during alcohol-induced injury can greatly impact the BBB and AD pathology. In AD transgenic mice, peripheral TNF-α blockage by the TNFR-Fc fusion protein (etanercept) reduces AD pathology, and our exciting preliminary data shows enhanced Aβ(1-42) migration across the brain endothelium due to TNF-α-mediated increase in BBB-permeability in vitro. This proposal will explore these novel findings to provide an integrated examination of how alcohol intake may alter the liver-to-brain axis to induce and/or promote AD pathology. The proposal has two specific aims: 1) Delineate the effect of alcohol on Aβ clearance by the liver and examine its impact on peripheral-to-central Aβ homeostasis. Our working hypothesis is that alcohol intake alters hepatic peripheral Aβ clearance through LRP1 downregulation to increase peripheral-to-central Aβ load. 2) Characterize the effect of alcoholic-liver-injury- induced peripheral inflammation on neurovascular- and neuronal-degeneration, and its impact on AD pathology. Our working hypothesis is that alcoholic-liver-injury-induced peripheral inflammation causes BBB dysfunction, increases AD hallmark pathology (Aβ and tau-tangles), and modulates neuroinflammation, thereby inducing and/or potentiating AD pathology. The proposal will combine specialists in the areas of liver/alcohol research with those in AD/BBB research to provide a comprehensive exploration of the liver-to-brain axis utilizing state- of-the-art in vivo and in vitro techniques and models, which will increase synergy and likelihood of success. The resulting new knowledge will enable the identification of new therapeutic-targets and provide mechanistic insight into alcohol-dependent AD, and will delineate the importance of the liver-to-brain axis in AD pathology, an unexplored concept in the emerging field of alcohol-dependent AD.


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 = $0 )
2025	2024	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	5	6/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $514,431 )
2024	2024	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	4	10/27/2023	SUPPLEMENT FOR EXPANSION	$55,565
2024	2024	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	002	5	7/9/2024	SUPPLEMENT FOR EXPANSION	$83,347
2024	2024	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	001	5	7/8/2024	NON-COMPETING CONTINUATION	$375,519
														Subtotal = $514,431

Issue Date FY: 2023 ( Subtotal = $427,374 )
2023	2023	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	4	7/11/2023	NON-COMPETING CONTINUATION	$427,374
														Subtotal = $427,374

Issue Date FY: 2022 ( Subtotal = $482,152 )
2022	2022	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	001	3	6/2/2022	NON-COMPETING CONTINUATION	$378,443
2022	2022	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	2	2/16/2022	SUPPLEMENT FOR EXPANSION	$25,927
2022	2022	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	002	3	6/3/2022	SUPPLEMENT FOR EXPANSION	$77,782
														Subtotal = $482,152

Issue Date FY: 2021 ( Subtotal = $476,001 )
2021	2021	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	003	2	6/24/2021	SUPPLEMENT FOR EXPANSION	$85,083
2021	2021	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	002	2	6/17/2021	NON-COMPETING CONTINUATION	$390,918
2021	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	001	1	12/2/2020	NEW	$0
2021	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	1	10/20/2020	NEW	$0
														Subtotal = $476,001

Issue Date FY: 2020 ( Subtotal = $387,994 )
2020	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	1	9/15/2020	NEW	$387,994
														Subtotal = $387,994

Grand Total All Awards = $2,287,952

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Modulation of the liver-brain axis by alcohol and its impact on Alzheimers disease pathology

Award Number: R01AG072896

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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