# Project 2: 3-D Molecular atlas of AD proteinopathy

> **NIH NIH U19** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $551,383

## Abstract

PROJECT 2: PROJECT SUMMARY/ABSTRACT
Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease of aging, and results in a variety
of symptoms, the most prominent of which is progressive cognitive decline. Whereas the primary pathological
proteinopathies associated with AD are aggregates of amyloid-beta (plaques) and tau (neurofibrillary
tangles), the appearance, density, and distribution of these proteinopathies shows substantial heterogeneity
across individuals and brain regions. In addition, individuals often display co-occurrence of these two
proteinopathies with other protein aggregates such as TDP43 and alpha-synuclein; these latter two are
primarily associated with diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia and
Parkinson’s Disease, but their occurrence in AD is not rare. From our bulk and single-nucleus RNA-seq
studies on post-mortem tissue, we have identified specific cellular signatures/putative subtypes whose
abundance is associated with tangles and plaques. However, these bulk and single-nucleus experimental
approaches do not preserve spatial information about how these cell types are localized (or not) around
pathological inclusions, and thus generate an incomplete picture of how the cellular structure of the aged
brain is altered in the presence of AD pathology. Here, we aim to examine the spatial distribution and
organization of these cell types directly in intact human brain tissue using highly-multiplexed spatial methods.
We propose a combination of novel but demonstrably scalable protein and gene expression approaches to
study large volumes (300-micron thickness) of human tissue with combinations of these proteinopathies.
These large volumes are necessary to study the full impact of protein aggregates on the “highly local”
environment. Specifically, we use a combination of highly multiplexed antibody staining and genome-wide
spatial transcriptomics methods to examine our hypothesis on the reorganization of neuronal and glial cell
types around pathological inclusions, with a focus on the two major AD-associated proteinopathies (amyloid
and tau). Ultimately, this will generate a high-resolution atlas of cell types and gene expression signatures in
aged human brain tissue that are altered in the presence of protein aggregates commonly found in AD,
complementing many of the existing and ongoing bulk and single-nucleus RNA-seq studies in the field of
human neurodegeneration research.

## Key facts

- **NIH application ID:** 10935939
- **Project number:** 5U19AG074862-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vilas Menon
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $551,383
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935939

## Citation

> US National Institutes of Health, RePORTER application 10935939, Project 2: 3-D Molecular atlas of AD proteinopathy (5U19AG074862-02). Retrieved via AI Analytics 2026-07-27 from https://api.ai-analytics.org/grant/nih/10935939. Licensed CC0.

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