# Non-enzymatic post-translational modifications as drivers of AD pathology

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2024 · $711,627

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is the most common form of dementia, and its association with type 2 diabetes is
well established. However, the molecular mechanisms underlying this link are not fully understood.
Hyperglycemia and dysregulated glucose metabolism have been suggested as factors contributing to the
increased risk of AD. This project aims to investigate the role of glycated tau and advanced glycation end
products (AGEs) in AD pathology, neurotoxicity, aggregation, and neuroinflammation. The proposed research
will pursue the following aims: Aim 1: Investigate how tau proteoforms with specific saccharide modifications
control aggregation and neurotoxicity. Aim 2: Expand in vitro studies to other reactive dicarbonyl species
operating through a mechanism similar to glycation. Aim 3: Evaluate the effects of glycation, AGE structure,
and attachment of DOPEGAL on interneuronal transmission, inflammation, and mitochondrial
dysfunction/oxidative stress. These studies will use hiPSC-derived models and will be accompanied by
extensive biophysical and biochemical characterizations to develop a molecular understanding of the role of
non-enzymatic post-translational modifications in AD. Successful completion of these aims will enable a more
precise diagnosis of AD and can potentially lead to novel therapeutic approaches based on the perturbation of
non-enzymatic modifications of tau and other proteins implicated in neurodegenerative diseases. Overall, this
research will provide important insights into the molecular mechanisms of AD and may lead to the
development of new treatments for this devastating disease.

## Key facts

- **NIH application ID:** 10885594
- **Project number:** 1R01AG087295-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Maciej Walczak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $711,627
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885594

## Citation

> US National Institutes of Health, RePORTER application 10885594, Non-enzymatic post-translational modifications as drivers of AD pathology (1R01AG087295-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885594. Licensed CC0.

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