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

> **NIH NIH R01** · KECK GRADUATE INST OF APPLIED LIFE SCIS · 2022 · $25,927

## Abstract

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
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.

## Key facts

- **NIH application ID:** 10543357
- **Project number:** 3R01AG072896-02S2
- **Recipient organization:** KECK GRADUATE INST OF APPLIED LIFE SCIS
- **Principal Investigator:** DERICK S HAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $25,927
- **Award type:** 3
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543357

## Citation

> US National Institutes of Health, RePORTER application 10543357, Modulation of the liver-brain axis by alcohol and its impact on Alzheimers disease pathology (3R01AG072896-02S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10543357. Licensed CC0.

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