# Defective lysosome acidification in dystrophic neurites in Alzheimer's disease contributes to failure of autophagy

> **NIH NIH R56** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $738,781

## Abstract

Alzheimer’s disease is a national crisis and the burden of this terrible disease is rising. After
decades of failure to produce a disease modifying treatment for Alzheimer’s disease, it is critical
that we identify drug targets that are linked to causal mechanisms underlying the diverse
neuropathological substrates of Alzheimer’s disease. Our research focuses on the function of
lysosomes within an axonal structure called a dystrophic neurite. Dystrophic neurites form when
axon segments pass near a β-amyloid plaque and become distended and clogged with
lysosomes and related organelles. Tau aggregates are also present in some dystrophic
neurites, so this pathology seems to link the major pathological hallmarks of Alzheimer’s
disease. Because lysosomes are critical for protein homeostasis, we hypothesize that loss of
function of these lysosomes is a key step in the formation of toxic protein aggregates. We
demonstrated a pattern of changes in the function this pool of lysosomes which could be
explained by failure of acidification, so in this proposal we will evaluate 1) whether lysosomes in
dystrophic neurites are able to acidify and what molecular mechanisms may underlie failed
acidification, 2) whether loss of lysosome acidification results in defective autophagy and
accumulation of pathologic autophagic intermediates within dystrophic neurites and 3) the
degree to which a novel Alzheimer’s disease genetic risk factor, RBFOX1, contributes to altered
autophagy and pH regulation in neuronal lysosomes. For each of these aims, we leverage
advanced in vitro methods including organotypic brain slice cultures from adult model animals
and three-dimensional human neuronal cultures derived from induced pluripotent stem cells
grown in a custom designed hydrogel matrix. Using live-imaging, we will quantitatively measure
the pH in lysosomes in dystrophic neurites. We will conduct detailed neuropathological studies
simultaneously in human and mouse model systems to identify altered distribution of vacuolar
ATPase subunits, ARL1 and Golgin A4 which are key regulators of autophagy, and RBFOX1.
Additionally, we want to understand the cognitive and neuropathological associations of each
component of the molecular pathways that contribute to failed acidification, defective autophagy
and tau aggregation, so we will leverage RNAseq and proteomic data from large clinical studies,
in particularly the Religious Orders Study/Memory and Alzheimer’s Project, to ensure these
pathways are functionally important. These synergistic streams of data will converge to robustly
establish the mechanism and consequence of loss of lysosome acidification in dystrophic
neurites and identify molecular targets for future drug discovery efforts.

## Key facts

- **NIH application ID:** 10670489
- **Project number:** 1R56AG074279-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Matthew Schrag
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $738,781
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670489

## Citation

> US National Institutes of Health, RePORTER application 10670489, Defective lysosome acidification in dystrophic neurites in Alzheimer's disease contributes to failure of autophagy (1R56AG074279-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10670489. Licensed CC0.

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