# Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $394,235

## Abstract

Abstract
Alcohol abuse damages liver, pancreas, heart, brain, and muscle. One severe outcome of alcohol abuse is
cognitive impairment and dementia. Although a role for alcohol in promoting Alzheimer's disease (AD) is
suspected, the underlying mechanisms are poorly understood. One proposed underlying mechanism in AD is
impaired or insufficient autophagy, an evolutionarily conserved lysosomal degradation pathway that regulates
organelle and protein homeostasis. Autophagy generally declines with age, resulting in an accumulation of
misfolded proteins including tau and β amyloid, as well as damaged mitochondria. Our recent work has
demonstrated that alcohol induces dysfunction of transcription factor EB (TFEB), a master regulator of
lysosomal biogenesis. Impaired TFEB leads to decreased lysosomal biogenesis and mitophagy resulting in
alcoholic hepatitis and pancreatitis. In addition to regulating autophagy, we also demonstrated that TFEB
increased mitochondrial biogenesis by up-regulating peroxisome proliferator-activated receptor gamma
coactivator 1-alpha (PGC1-α). More importantly, decreased nuclear TFEB levels is associated with human
alcoholic hepatitis and pancreatitis but its role in alcohol-associated AD has not been investigated. Our
preliminary results showed that alcohol decreased total and nuclear TFEB but increased ubiquitinated proteins
in mouse hippocampi. In addition, aged mice (22-months old) also have decreased nuclear TFEB staining but
increased p62 and phosphorylated Tau in the hippocampi compared with young mice (3-months old). These
collective observations suggest that alcohol consumption and aging may synergistically interact to perturb the
TFEB-lysosome biogenesis axis, thereby leading to impaired brain autophagy. Here, we hypothesize chronic
alcohol consumption compounds age-related decrease of TFEB-mediated lysosomal biogenesis in the brain,
which in turn leads to an accumulation of damaged mitochondria and protein aggregates. These phenomena
occur in AD, and our proposed experiments promise to establish links between brain aging, alcohol
consumption, and AD pathology. We further predict overexpression of TFEB and TFEB knockin transgenic
mice will protect against these brain aging and alcohol-induced pathologies. We also propose to assess
potential neuroprotective effects of novel TFEB agonists identified from a high-throughput screening that were
recently completed. The successful completion of the proposed work will provide a new paradigm of
uncovering the role of TFEB in autophagy and lysosome biology in alcohol-associated AD and brain aging.

## Key facts

- **NIH application ID:** 10132613
- **Project number:** 1R01AG072895-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Wen-Xing Ding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,235
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132613

## Citation

> US National Institutes of Health, RePORTER application 10132613, Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease (1R01AG072895-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132613. Licensed CC0.

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