# Probing Protein Structural Changes in Alzheimers Disease

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $420,010

## Abstract

ABSTRACT
In amyloidosis and neurodegenerative disorders, proteins undergoing structural changes have high propensity
to form insoluble deposits. These proteins convert from soluble functional states to highly organized fibrillary
aggregates, termed amyloid fibrils, becoming toxic to neurons. As the most common form of dementia,
Alzheimer’s disease (AD) is characterized as amyloid plaques composed of aggregated amyloid-β (Aβ) and
neurofibrillary tangles formed by hyperphosphorylation and aggregation of tau. Given that the accumulation of
protein aggregates is the common feature of progressive neurodegeneration diseases, we hypothesize that AD
may be associated with misfolding of some unknown proteins in an independent or synergistic way with Aβ. The
primary goal of this proposal is to explore the novel concept of “conformational biomarkers” and their
utility for AD diagnosis and monitoring disease progression. We will develop cutting-edge mass
spectrometry (MS)-based proteomics technologies to discover, characterize, and evaluate potential
conformational biomarkers of AD using cerebrospinal fluid (CSF). Different from classical concentration-based
disease biomarkers, conformational biomarkers reflect the changes in protein structure, directly revealing its
function during the disease progression. We aim to address the following questions: (1) Will some unknown
aggregation-prone proteins play important roles in Alzheimer’s disease? How to probe the structural transition
of these misfolding proteins in complex proteomes? (2) How to evaluate the validity of putative conformational
biomarkers resulting from non-targeted CSF analysis? (3) How to establish correlation between these putative
protein conformational biomarkers and pathological features in Alzheimer’s disease? Can we use them to
monitor disease progression or degree of cognitive impairment?
 To address these questions, we propose the following specific aims: Specific Aim 1 – To perform global
proteomic and post-translational modification analysis of CSF samples obtained from age-matched cognitively-
healthy subjects, asymptomatic preclinical individuals, and patients with mild cognitive impairment (MCI) and
dementia, to probe protein structural transitions and dynamic changes in AD. Specific Aim 2 – To validate the
conformational biomarkers with targeted quantitative proteomic approaches in CSF and plasma samples.
Specific Aim 3 – To evaluate and establish the correlation between conformational biomarkers and pathological
features including AD-related clinical, cognitive and neuroimaging measures. Collectively, our proposed
experiments will be the first system-wide, large-scale analysis of protein structure changes in AD. The newly
discovered and validated conformational biomarkers would be invaluable in exploring molecular mechanism and
designing therapeutic targets in Alzheimer’s disease.

## Key facts

- **NIH application ID:** 9877119
- **Project number:** 1R21AG065728-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** LINGJUN LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,010
- **Award type:** 1
- **Project period:** 2020-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877119

## Citation

> US National Institutes of Health, RePORTER application 9877119, Probing Protein Structural Changes in Alzheimers Disease (1R21AG065728-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9877119. Licensed CC0.

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