# NOVEL EXOSOME BIOMARKERS OF IRON PATHOLOGY IN AD

> **NIH NIH R21** · STANFORD UNIVERSITY · 2021 · $433,029

## Abstract

PROJECT SUMMARY/ABSTRACT
 Alzheimer’s disease (AD) afflicts millions of Americans, yet no effective treatments exist. Iron has been shown
to be involved in key AD pathologic processes, including amyloid and tau aggregation, inflammation, oxidative
stress, and cell death mechanisms. Despite this growing evidence, it is challenging to ascertain alterations in
iron metabolism in vivo, limiting potential translation to biomarkers and novel therapies. Exosomes are
nanometer-sized vesicles shed by cells to transport proteins, nucleic acids, metals, lipids or metabolites. While
exosomes reflect cellular processes and can reveal disease-related pathologies in human tissues and biofluids,
iron abnormalities in AD exosomes have not yet been investigated. We will address this knowledge gap through
state-of-the-art exosome isolation technology combined with advanced iron imaging, protein quantification and
next generation sequencing methods. Our goal is to investigate iron dysregulation in exosomes from post-
mortem AD brains, in order to unveil AD-specific biomarkers and facilitate the development of novel therapies.
 The project aims are: (1) To determine whether the quantity, oxidation state, and cellular origin of exosomal
iron is altered in AD. Using MRI and synchrotron X-ray microscopy, we will quantify tissue iron content and
oxidation state in human AD and control hippocampal specimens. We will then use our novel exosome
isolation platform, ExoTIC, to isolate exosomes from regions of high hippocampal iron content in the same
specimens. Using antibodies that target cell-surface proteins, we will enrich the isolated exosomes based on
their cellular origin (e.g. neurons, microglia, etc.). We will quantify exosomal iron content from each cell type
using mass spectrometry (ICP-MS), and measure exosomal iron oxidation state using electron microscopy.
Taken together, we will determine whether iron content and oxidation state are altered in Alzheimer’s
exosomes compared to controls, in particular in exosomes originating in microglia, the brain’s immune cells.
(2) Detect dysregulation of iron-related proteins and RNAs in AD exosomes. Using Western blotting on the
enriched exosomes, we will determine whether levels of proteins that play a role in iron metabolism are altered
in AD compared to controls. Because exosomes are generally rich in microRNAs that are known to regulate
gene expression, we will use RNA-Seq to determine whether exosomal microRNAs regulating these same
iron-related proteins are also altered in AD. Machine learning algorithms will enable the creation of an atlas of
microRNAs linking iron, iron-related proteins, and neuropathology, which should provide a deeper
understanding of AD biology.
 Characterization of exosome content in the AD brain should result in cell-specific signatures of iron
dysregulation associated with neurodegeneration. This approach may elucidate novel aspects of AD biology,
lead to novel assays to detect early AD, and fa...

## Key facts

- **NIH application ID:** 10223789
- **Project number:** 1R21AG072675-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Utkan DEMIRCI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,029
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223789

## Citation

> US National Institutes of Health, RePORTER application 10223789, NOVEL EXOSOME BIOMARKERS OF IRON PATHOLOGY IN AD (1R21AG072675-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10223789. Licensed CC0.

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