# Molecular impact of endolysosomal dysfunction on neuron-glia communication pathways

> **NIH NIH F32** · BOSTON CHILDREN'S HOSPITAL · 2024 · $74,284

## Abstract

Project Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia worldwide.
Despite decades of research, there are few therapies that can delay or prevent AD progression. Retrograde
trafficking through retromer-dependent cargo recognition has emerged as a critical cellular process that is
mutated or disrupted in patients with AD and other forms of dementia. Conditional knockout of retromer genes
in neurons leads to increased secretion of Tau and Amyloid β (Aβ), hallmark protein pathologies linked to AD.
This milieu of neuronal-secreted factors leads to inflammation in microglia and astrocytes, two glial cell types
thought to influence the progression of neurodegeneration. In this proposal, I aim to study the cascade of events
linking neuronal retromer disruption to glial inflammation, characterizing the specific cell state changes involved,
and identify the key factors that mediate this effect. I will address this aim using genetically engineered stem cell-
derived models of human neurons, microglia, and astrocytes. Microglia also express retromer components and
upregulate these factors in AD, yet there are few studies of retromer function specifically in microglia. In Aim 2 I
will therefore explore the effects of retromer-related mutations specifically on microglia in the context of early
aging in mice, a comparable time point to when dementia manifests in patients with these mutations. I will
additionally utilize stem cell models to dissect the functional and signaling changes that are induced in microglia
with retromer disruption. Finally, although there have been several studies looking at the effects of retromer on
specific receptors, little is known about the systems-level effects of retromer mutations on protein trafficking to
the endosomes. To identify retromer-dependent signaling pathways that may be pathogenic, I have developed
novel proteomics tools to quantify endosomal proteome changes and will use these tools to compare the effects
of different retromer mutations on neuronal and microglial endosomes. The ultimate goal is to understand how
retromer disruption affects brain cell states and leads to pathogenic signaling changes.

## Key facts

- **NIH application ID:** 10770360
- **Project number:** 5F32AG079666-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Nader Francis Morshed
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-01-29 → 2025-04-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770360

## Citation

> US National Institutes of Health, RePORTER application 10770360, Molecular impact of endolysosomal dysfunction on neuron-glia communication pathways (5F32AG079666-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10770360. Licensed CC0.

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