# Architecture of Alzheimer's Disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $467,593

## Abstract

Project Summary
The brain is composed of unique cell types, such as neurons and astrocytes, that actively coordinate to enable
higher order functions including learning, memory, and cognition. Even slight deviances in the molecular or
cellular states of the brain can result in debilitating neurological symptoms whose severity, treatment course,
and overall treatment outcome vary widely from patient to patient. This level of complexity likely contributes to
promising therapeutics failing within clinical trials and, thus, requires further exploration. To date, most of our
foundational knowledge of neuroscience stems from a neuron-centric focus. Recent literature has demonstrated
that other cell types, such as astrocytes, may participate in signaling and communication beyond their known
passive, supporting roles. As such, exploring the molecular and cellular diversity of astrocytes in their native
tissue context will help us better understand neurological function and dysfunction, particularly in Alzheimer’s
disease (AD). Because of the inherent spatial and chemical complexity in physiological processes and
interconnectedness of cells, we will develop workflows for integrating multiresolution and multimodal imaging
methods for the characterization of spatial relationships among cell phenotypes in AD compared to healthy
controls. To investigate the molecular diversity within the hippocampus, we are employing a combination of mass
spectrometry imaging (MSI) and multiplexed immunofluorescence (MxIF) to gain rich metabolomic information
that is associated with cell type and state. MSI can detect hundreds to thousands of endogenous molecules
while maintaining their spatial distributions. While chemically informative, these datasets are often difficult to
correlate directly to cell type or functional state without an orthogonal technique, such as immunohistochemistry.
Because the number of cell types exceed what can be probed by traditional IF approaches within a single
experiment, we have chosen to incorporate MxIF, using Cell DIVE, to increase the number of imageable targets
compared to traditional fluorescence microscopy. By staining for traditional cell-specific markers, we can use
MxIF to connect metabolomic profiles uncovered using MSI to functionally important cellular neighborhoods in
AD. Ultimately, we will establish small molecule, lipid, and cellular spatial differences between hippocampal
regions of AD and control subjects using high spatial resolution MALDI mass spectrometry imaging (MSI) and
highly multiplexed immunofluorescence (MxIF) (aim 1) as well as integrate multimodal data sets to examine the
molecular neighborhoods associated with typical and atypical cellular neighborhoods surrounding astrocytes
within AD (aim 2). By conclusion of these two aims, we will have developed workflows for integrating MSI and
MxIF on the cortex from human AD and control subjects to identify molecular and cellular phenotypes and
characterize their spatial r...

## Key facts

- **NIH application ID:** 10885298
- **Project number:** 1R21AG083965-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Elizabeth Kathleen Neumann
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,593
- **Award type:** 1
- **Project period:** 2024-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885298

## Citation

> US National Institutes of Health, RePORTER application 10885298, Architecture of Alzheimer's Disease (1R21AG083965-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885298. Licensed CC0.

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