# Concordance of TDP-43 Inclusions with Cortical Atrophy and Clinical Phenotype

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $685,581

## Abstract

Project Summary
Aggregation and propagation of misfolded proteins in the form of abnormal inclusions is a common feature of
numerous neurodegenerative diseases. A majority of brains with frontotemporal lobar degeneration (FTLD) are
characterized by mislocalization and aggregation of transactivation response element DNA binding protein-43
(TDP-43) into insoluble inclusions. Given that TDP-43 is among the most recently identified pathologic
precipitates, the goal of Cycle 1 of this project was to explore the relationship between TDP-43 inclusions,
cellular alterations, cortical atrophy and disease phenotype in FTLD and in a conditionally transgenic mouse
model expressing wild-type human (h) TDP-43 in the forebrain. We observed that density of TDP-43
inclusions, neuronal shrinkage, and density of activated microglia in cortical gray and white matter are
concordant with patterns of cortical atrophy and disease phenotype and that TDP-43 inclusions may spread
trans-synaptically. In TDP-43 transgenic mice, we confirmed regionally selective cortical atrophy, and
progressive TDP-43 accumulation and inclusion formation, gliosis, apoptosis and behavioral alterations
consistent with the pathologic and behavioral alterations in FTLD. Importantly, the density of activated
microglia displayed the closest and most consistent relationship with cortical atrophy and disease phenotype in
FTLD. Cycle 2 of this project builds upon the observations during Cycle 1 and will focus on the role of microglia
/ immune activation, including synaptic pruning as disease spreads. We will conduct a comprehensive survey
of microglia / immune gene and protein expression changes in brains of FTLD and hTDP transgenic mice, will
explore alterations in synapses and synaptic proteins in FTLD and potential role of microglia mediated pruning
in synaptic loss, and will investigate the role of microglia generated exosomes in spread of TDP-43 pathology
in the mouse model. We propose to base this investigation on rigorous quantitative methods, including
unbiased stereological quantification and RNA sequencing (RNAseq) in a unique set of autopsy specimens
with extensive clinical and pathological information and in a mouse model which recapitulates features of
human disease. The specific aims of the proposed research will test the following hypotheses: Aim 1. FTLD-
TDP and hTDP-43 transgenic mouse brains will display regionally selective alterations in microglia
transcriptome and associated immune proteins. Aim 2. FTLD-TDP and hTDP-43 transgenic mice will display
substantial, early and regionally specific loss of synapses that is due in part to abnormal synaptic pruning by
microglia. Aim 3. hTDP-43 transgenic mice will display trans-synaptic spread of TDP-43 pathology over time in
the hippocampus and microglia derived exosomes facilitate this spread in the hippocampus and across cortex.
The proposed research will generate a great deal of information on the status of synapses and potential trans-...

## Key facts

- **NIH application ID:** 9923902
- **Project number:** 2R01NS085770-06
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** CHANGIZ GEULA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $685,581
- **Award type:** 2
- **Project period:** 2014-08-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923902

## Citation

> US National Institutes of Health, RePORTER application 9923902, Concordance of TDP-43 Inclusions with Cortical Atrophy and Clinical Phenotype (2R01NS085770-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9923902. Licensed CC0.

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