# Mechanism of cell uptake for pathogenic tau seeds

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $680,077

## Abstract

Alzheimer’s and related neurodegenerative diseases are a major health problem. The tau protein is known to
play a critical role in these disorders. In the disease state tau transitions from a normal, “healthy” three-
dimensional shape to one that is capable of self-assembling into pathological aggregates. Remarkably, these
aggregates, once formed in a brain cell, appear to exit that cell and gain entry into neighboring or connected
cells, where they can serve as disease-causing “templates” to corrupt normal tau protein to an abnormal
conformation. Free tau aggregates can bind the cell surface by interacting with specific proteins called heparan
sulfate proteoglycans (HSPGs), which are modified in the cell through the attachment of sugar molecules,
which themselves are modified by the addition of sulfate groups. These modifications occur during the
synthesis of HSPGs, and depend on specific cellular enzymes. One enzyme, NDST1, was previously identified
as being very important for enabling HSPGs to be properly modified so as to bind tau protein. Once bound to
HSPGs, tau assemblies get into the cell, where they create more aggregates. The mechanisms by which tau
can cross the cell membrane are unknown. It is also unknown whether the mechanisms that apply to tau are
similar to those that function for other disease-causing proteins. This grant will test the role of NDST isoforms
in a mouse model of tau-induced neurodegeneration to see if the pathway implicated by prior studies might be
targeted to create new drugs for Alzheimer’s. Additionally, the grant will determine how tau assemblies can
cross the cell membrane, and whether mechanisms that apply to tau also apply to other disease-causing
proteins.

## Key facts

- **NIH application ID:** 10769762
- **Project number:** 5R01AG071502-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** MARC I DIAMOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $680,077
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769762

## Citation

> US National Institutes of Health, RePORTER application 10769762, Mechanism of cell uptake for pathogenic tau seeds (5R01AG071502-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10769762. Licensed CC0.

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