# Characterization of AD-related endolysosomal dysfunction in human neural cells

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $851,663

## Abstract

Project Summary
Alzheimer’s disease (AD) is a major leading cause of death in the developed world and there are few preventative
or disease-modifying treatments. Genetics and cell biology point to deficiencies in the endo-lysosomal network
as a driving factor in AD pathogenesis. Therefore, this proposal is in response to NOSI (NOT-AG-21-034):
Genetic Underpinnings of Endosomal Trafficking as a Pathological Hub in AD/ADRD. We will use human
induced pluripotent cell lines (hiPSC) and patient tissue to define how endo-lysosomal dysfunction impacts cell-
type specific functions and how high genetic burden of risk in endo-lysosomal pathways manifests in the AD
brain.
In Aims 1 and 2 we will perform experiments in neurons and microglia harboring AD-associated variants in the
endosomal gene SORL1. SORL1 is a highly pathogenic AD risk gene and mutations in SORL1 that lead to
haploinsufficiency are considered causal for AD. SORL1 is also a strong risk factor late onset AD. The protein
product of the SORL1 gene, SORL1/SORLA interacts with the multi-protein sorting complex retromer to traffic
various cargo essential for cellular function. Understanding the impact of SORL1-retromer trafficking in diverse
cell types of the central nervous system is essential to determine whether this is a valid therapeutic pathway. We
will differentiate neurons and microglia from hiPSCs harboring AD-associated variants in SORL1, along with
isogenic controls. In these cells we will perform assays to specifically interrogate neuronal and microglial
functions that rely on efficient endo-lysosomal trafficking. For neurons we will test neuronal synaptic function and
analysis of protein-protein interactions at the neuronal synapse. For microglia we will test phagocytosis,
lysosomal degradation, receptor recycling and cytokine levels. In both cell types, we will test whether aberrant
phenotypes can be rescued by using small molecules that enhance retromer function and by genetically
expressing specific components of the SORL1-retromer pathway.
For Aim 3 we have also generated a cohort of patient-derived hiPSC lines from late onset AD subjects and
controls and matched brain tissue stratified by polygenic risk in the endo-lysosomal network (ePRS). We will
analyze endo-lysosomal phenotypes in brain tissue as well as in neural cells differentiated from the matched
hiPSC lines. We will test whether rescue of ELN trafficking via the SORL1-retromer pathway will also be
beneficial in these cell lines. These experiments will significantly advance knowledge in this area by generating
patient-specific data on global gene expression and morphology in a cohort representative of the genomes of at-
risk individuals. These experiments will also be critical in determining whether this pathway can be a strong
target for AD therapeutic development.

## Key facts

- **NIH application ID:** 10804847
- **Project number:** 1R01AG080585-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** SUMAN JAYADEV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $851,663
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804847

## Citation

> US National Institutes of Health, RePORTER application 10804847, Characterization of AD-related endolysosomal dysfunction in human neural cells (1R01AG080585-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804847. Licensed CC0.

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