# Spatial Transcriptomics for Investigating the Interaction between TDP-43 Proteinopathy and Hippocampal Sclerosis in Alzheimer's Disease

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $242,290

## Abstract

PROJECT SUMMARY
 Alzheimer's Disease (AD) stands as a formidable neurodegenerative affliction impacting millions globally.
While substantial headway has been made in deciphering the genetic and molecular underpinnings of AD, critical
questions persist regarding transcriptomic responses to hippocampal sclerosis (HS) and TAR DNA-binding
protein of 43 kDa (TDP-43) proteinopathy, two established features of the disease. Aberrant gene expression
has been linked to both HS and TDP-43 proteinopathy. Different TDP-43 species have been found to have
distinct binding abilities to specific RNA regions and thus selectively influence its RNA-regulatory network. HS is
accompanied by the disruption of the gene regulatory network involved in neuronal apoptosis. However, the
transcriptomic impact of their interplay remains unexplored. Recently, we have characterized a unique
phosphorylation-independent anti-TDP-43 monoclonal antibody specific for a new TDP-43 species in
frontotemporal lobar degeneration (FTLD)-TDP type A and type B. The goal of this proposal is to investigate the
regional and transcriptomic bases of the contribution of the new TDP-43 species and HS to AD. Our central
hypothesis is that the interplay between TDP-43 proteinopathy and HS influences hippocampal transcriptomic
abnormalities. In this study, we propose to combine the strengths of the unique anti-TDP-43 antibody and the
state-of-the-art spatial sequencing developed to investigate the transcriptomic aspects of how novel TDP-43
species contribute to HS in AD. Aim 1 will quantitatively analyze the distributions of TDP-43 proteinopathy (new
TDP-43 species) and neuronal loss in the hippocampi of AD brains. Aim 2 will determine hippocampal gene
expression profiles associated with the new TDP-43 species using spatial sequencing technologies. The
successful execution of this project will significantly advance our understanding of TDP-43 research, particularly
in terms of our limited knowledge concerning pathologic TDP-43 species and its intricate association with HS in
AD.

## Key facts

- **NIH application ID:** 10946790
- **Project number:** 1R21AG088509-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Qinwen Mao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $242,290
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946790

## Citation

> US National Institutes of Health, RePORTER application 10946790, Spatial Transcriptomics for Investigating the Interaction between TDP-43 Proteinopathy and Hippocampal Sclerosis in Alzheimer's Disease (1R21AG088509-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10946790. Licensed CC0.

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