# Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease.

> **NIH NIH K76** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $243,000

## Abstract

Alzheimer’s disease (AD) compromises the independence of aging adults and is associated with huge societal
burden in healthcare and caregiver costs. An effective treatment is urgently needed to stem the tide of the
ongoing and growing epidemic of dementia. Many recent clinical trials have attempted to reduce the level of β-
amyloid in the brain, typically by activating the immune system to promote clearance, yet none of these trials
has been successful. We propose to explore this problem in a different way – we discovered that neuronal
axons around deposits of β-amyloid are swollen and filled with abnormal lysosomes which are deficient in
protein-degrading enzymes. Because lysosomes are critical for protein homeostasis, we hypothesize that
these abnormal lysosomes contribute to neurodegeneration and if their function could be rescued, it could
improve brain function. We will study this hypothesis by focusing on a novel gene, PLD3, which was identified
as contributing to AD risk. In our preliminary work, we discovered that PLD3 is robustly enriched on these
abnormal lysosomes and brain PLD3 levels correlated inversely with both β-amyloid burden and the rate of
cognitive deterioration in a human cohort. Brain PLD3 levels also correlated inversely with memory
performance in a mouse model. We discovered that PLD3 functions as a phospholipase D in acidic
environments and is necessary for lysosomal membrane fission. We propose to evaluate to what degree the
lysosome dysfunction observed in mice is present in human tissue and to fully evaluate the association of
PLD3 with neuronal lysosomal pathology. We will then determine whether the coding variants reported to
confer AD-risk impact the function of PLD3 by transfecting plasmids containing PLD3 (which have been
mutated to copy these coding variants) and observing the effect on lysosomal membrane fission and on PLD3
enzyme activity. We will determine whether defective neuronal lysosomal fission impacts cognition and AD
neuropathology in vivo by crossing the 5xFAD model of genetic AD with a conditional knock-out of Fig4 using a
Cre selectively expressed in cerebral neurons. Fig4 is a component of the PIKfyve complex and loss of Fig4
leads to defective lysosomal fission. Importantly, the PIKfyve complex also regulates PLD3 processing and
alters PLD3 activity. We will evaluate learning and memory in this mouse and determine whether defective
lysosomal fission impacts β-amyloidosis and dystrophic neurites. These studies will help us understand both
how this protein functions in the setting of AD and the role of lysosome membrane fusion in cognitive aging
and AD. The parallel training plan will support my training in model animal development and behavioral
phenotyping, developing advanced skills in lyosomal neurobiology and refine clinical management of aging
related diseases, all of which are critical steps for my career development. Collectively, the outstanding
institutional environment, resources, and in...

## Key facts

- **NIH application ID:** 10406342
- **Project number:** 5K76AG060001-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Matthew Schrag
- **Activity code:** K76 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406342

## Citation

> US National Institutes of Health, RePORTER application 10406342, Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease. (5K76AG060001-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10406342. Licensed CC0.

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