# Glysocaminoglycan Modifications as Regulators of Alzheimer's Disease-Related Pathologies

> **NIH NIH R21** · PENNSYLVANIA STATE UNIVERSITY, THE · 2022 · $197,738

## Abstract

Project Summary/Abstract
As described by the High Priority Research Topics for this RFA, there is compelling evidence
that glycosylation plays “critical roles in the early pathogenesis and progression of AD” yet the
“potential of these molecules to serve as biomarkers and targets of disease intervention remains
largely unexplored”. Specific areas of program relevance included the “role of extracellular
matrix and proteoglycans in … accumulation of AD-related pathologies”. These areas are
topics my laboratory has recently explored and my group has been involved in establishing the
biological functions of heparan sulfate modified proteins over the last 20 years. In recent work
we have shown that heparan sulfate proteoglycans regulate membrane trafficking, including
autophagy, endocytosis and mitochondrial surveillance(1), processes central to
neurodegenerative pathology. We have shown that modest changes in heparan sulfate
structure, such as sulfation state or chain length, can increase catabolic membrane trafficking,
including delivery of autophagosomes to the lysosome. These findings suggest that changing
heparan sulfate structure could counteract the cellular processes that are compromised in AD
and related pathologies. This hypothesis is supported by our demonstration that partial
reductions in specific heparan sulfate modifying enzyme encoding genes can suppress cell loss
in three distinct Drosophila models of neurodegenerative diseases(2) including AD. It is
important to point out that the level of these changes do not disrupt developmental patterning
but actually confers increased lifespan and resistance to oxidative stress. Using a panel of
CRISPR-generated mutant human cell lines affecting heparan sulfate biosynthesis we have
shown that the regulation of membrane trafficking by these molecules is conserved in human
cells. We now wish to extend these observations into medically relevant models of AD to
determine if heparan sulfate biosynthesis is a viable therapeutic target for AD and related
pathologies. These studies employ both iPSC-derived neurons bearing mutations in known AD
susceptibility genes (presenilin and APP), and a Drosophila model of age-dependent
neurodegeneration, where conditional knockdown of presenilin function is achieved in adult
neurons. In both of these systems we propose to determine if changes in heparan sulfate
biosynthesis achieved by targeted knockdown of key biosynthetic enzyme encoding genes can
achieve rescue of cellular phenotypes, and reverse the alterations in autophagy, mitophagy, and
membrane trafficking that have been observed in human tissues as well as iPSC-derived
neurons from patients.

## Key facts

- **NIH application ID:** 10461886
- **Project number:** 5R21AG070843-02
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** SCOTT B SELLECK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $197,738
- **Award type:** 5
- **Project period:** 2021-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461886

## Citation

> US National Institutes of Health, RePORTER application 10461886, Glysocaminoglycan Modifications as Regulators of Alzheimer's Disease-Related Pathologies (5R21AG070843-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461886. Licensed CC0.

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