# Axonal endo-lysosome transport mechanisms that regulate APP processing

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

Our research will take a cell biology approach to investigate mechanisms controlling axonal lysosome transport
and maturation. Through these efforts we will seek to define how defects in the axonal transport and
maturation of lysosomes create a sub-cellular environment that is highly conducive to the amyloidogenic
processing of APP and the development of amyloid plaque pathology. These efforts are motivated by human
genetics studies that have identified multiple genes encoding endo-lysosomal pathway proteins as AD risk
factors as well as the well established but poorly understood local accumulation of lysosomes within swollen
axons that surround amyloid plaques. Although such lysosome accumulations are widely found in human AD
brain tissue and are recapitulated in transgenic mouse models that develop amyloid plaques, the contributions
of these lysosomes (either protective or deleterious) on disease progression or dementia are not known.
Based on our previous investigation of the amyloid plaque-associated axonal lysosome accumulations
and axonal lysosome transport mechanisms, we hypothesize that defects in axonal lysosome
transport and maturation create hotspots for amyloidogenic APP processing. Therefore, to investigate
the contribution of defective axonal lysosome transport to APP processing and Aβ peptide production, we aim
to: (1) Define mechanisms that control axonal lysosome abundance; (2) Establish the impact of axonal
transport defects on amyloid precursor protein processing, Aβ production and the development of amyloid
plaque pathology. Central to these proposed studies is our recent discovery of a robust defect in the
coordinated process of axonal lysosome transport and maturation in neurons from JNK-interacting protein 3
(JIP3) knockout mice. Through our proposed efforts to dissect the mechanisms whereby JIP3 regulates axonal
lysosomes and their ability to serve as sites of APP processing, we will gain new insight into possible
pathogenic roles played by these organelles in Alzheimer's disease. Focusing on this specific subcellular
environment that is so supportive of the amyloidgenic processing of APP has the potential to identify new
strategies to specifically suppress the most dangerous sub-cellular sites for APP processing while sparing
potentially beneficial functions of genes such as APP, BACE1 and PSENs. This research could thereby lead to
novel therapeutic opportunities focused on manipulating axon lysosome biogenesis and/or transport to limit
both Aβ production and neuronal pathology. New insights into the cell biology of neuronal lysosomes revealed
by the proposed studies are expected to have additional broad relevance to other neurodegenerative diseases
with lysosomal contributions to their pathology such as Parkinson's disease, frontotemporal dementia and
hereditary spastic paraplegia.

## Key facts

- **NIH application ID:** 10219145
- **Project number:** 5R01AG062210-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SHAWN FERGUSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219145

## Citation

> US National Institutes of Health, RePORTER application 10219145, Axonal endo-lysosome transport mechanisms that regulate APP processing (5R01AG062210-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219145. Licensed CC0.

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