TDP-43 Coincides with Noradrenergic Neurons in Alzheimer’s Disease (AD) and Primary Age-Related Tauopathy (PART)
5 affiliations
- 1Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
- 2Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
- 3Department of Neuropsychiatry (Neuropsychology), Mayo Clinic, Rochester, MN 55905, USA
- 4Department of Laboratory Medicine and Pathology (Neuropathology), Mayo Clinic, Rochester, MN 55905, USA
- 5Department of Neurology, Behavioral Neurology, and Movement Disorders, Mayo Clinic, College of Medicine, and Science, 200 1st Street Southwest, Rochester, MN 55905, USA
Abstract
TAR DNA-binding protein 43 (TDP-43) pathology is a major contributor to cognitive decline in Alzheimer’s disease (AD), yet the cellular substrates and circuit-level consequences of its limbic accumulation remain poorly defined. Here, we combined multiplex immunofluorescence with 3D Artificial Intelligence (AI)-based object detection and quantitative colocalization to map phosphorylated TDP-43 (pTDP-43) across neuronal subtypes in the amygdala, hippocampal subfields, and entorhinal cortex (ERC) in human AD, AD with Lewy body disease (AD-LBD), and primary age-related tauopathy (PART). Across 15 deeply phenotyped cases, pTDP-43 showed preferential accumulation in neuromodulatory noradrenergic neurons, with more limited involvement of glutamatergic terminals and cholinergic populations. Noradrenergic neurons marked by dopamine β-hydroxylase (DβH) demonstrated extensive colocalization with pTDP-43 across regions, correlating with APOE genotype, amyloid burden, and tau staging in this cross-sectional cohort, suggesting that neuromodulatory circuits might represent a major convergence point for AD-related molecular stressors. Dopaminergic (tyrosine hydroxylase (TH)) and cholinergic (choline acetyltransferase (ChAT)) neurons showed more restricted but pathology-dependent involvement, with LBD consistently showing lower pTDP-43 burden across multiple transmitter systems. Glutamatergic vesicular glutamate transporter-1 (VGLUT1)-positive neurons and terminals exhibited minimal colocalization except in PART. Principal component (PCA) and hierarchical clustering analyses (HCA) integrating pTDP-43 colocalization with neuropathologic staging metrics (A, B, C, Thal, Braak, LBD) reliably separated PART, AD-TDP, and AD-TDP-LBD groups, with LBD emerging as a dominant modifier of cellular vulnerability. Together, these findings point out that TDP-43 pathology in AD preferentially targets neuromodulatory circuits, is strongly shaped by coexisting synucleinopathy, and provides a cell-type-resolved framework for understanding how TDP-43 contributes to limbic network dysfunction in neurodegeneration.
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BibTeX
@article{uruk2026tdp43,
title = {{TDP-43 Coincides with Noradrenergic Neurons in Alzheimer’s Disease (AD) and Primary Age-Related Tauopathy (PART)}},
author = {Gokhan Uruk and Hossam Youssef and Rodolfo G. Gatto and Nadia Hossain and Jerusha Bhaskaran and Yuqi Tian and Mary M. Machulda and Ronald C. Petersen and Jennifer L. Whitwell and Robert Ross Reichard and Keith A. Josephs},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201850},
url = {https://www.mdpi.com/2073-4409/15/20/1850},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TDP-43 Coincides with Noradrenergic Neurons in Alzheimer’s Disease (AD) and Primary Age-Related Tauopathy (PART)
AU - Gokhan Uruk
AU - Hossam Youssef
AU - Rodolfo G. Gatto
AU - Nadia Hossain
AU - Jerusha Bhaskaran
AU - Yuqi Tian
AU - Mary M. Machulda
AU - Ronald C. Petersen
AU - Jennifer L. Whitwell
AU - Robert Ross Reichard
AU - Keith A. Josephs
PY - 2026
DA - 2026/10/12
JO - Cells
DO - 10.3390/cells15201850
UR - https://www.mdpi.com/2073-4409/15/20/1850
AB - TAR DNA-binding protein 43 (TDP-43) pathology is a major contributor to cognitive decline in Alzheimer’s disease (AD), yet the cellular substrates and circuit-level consequences of its limbic accumulation remain poorly defined. Here, we combined multiplex immunofluorescence with 3D Artificial Intelligence (AI)-based object detection and quantitative colocalization to map phosphorylated TDP-43 (pTDP-43) across neuronal subtypes in the amygdala, hippocampal subfields, and entorhinal cortex (ERC) in human AD, AD with Lewy body disease (AD-LBD), and primary age-related tauopathy (PART). Across 15 deeply phenotyped cases, pTDP-43 showed preferential accumulation in neuromodulatory noradrenergic neurons, with more limited involvement of glutamatergic terminals and cholinergic populations. Noradrenergic neurons marked by dopamine β-hydroxylase (DβH) demonstrated extensive colocalization with pTDP-43 across regions, correlating with APOE genotype, amyloid burden, and tau staging in this cross-sectional cohort, suggesting that neuromodulatory circuits might represent a major convergence point for AD-related molecular stressors. Dopaminergic (tyrosine hydroxylase (TH)) and cholinergic (choline acetyltransferase (ChAT)) neurons showed more restricted but pathology-dependent involvement, with LBD consistently showing lower pTDP-43 burden across multiple transmitter systems. Glutamatergic vesicular glutamate transporter-1 (VGLUT1)-positive neurons and terminals exhibited minimal colocalization except in PART. Principal component (PCA) and hierarchical clustering analyses (HCA) integrating pTDP-43 colocalization with neuropathologic staging metrics (A, B, C, Thal, Braak, LBD) reliably separated PART, AD-TDP, and AD-TDP-LBD groups, with LBD emerging as a dominant modifier of cellular vulnerability. Together, these findings point out that TDP-43 pathology in AD preferentially targets neuromodulatory circuits, is strongly shaped by coexisting synucleinopathy, and provides a cell-type-resolved framework for understanding how TDP-43 contributes to limbic network dysfunction in neurodegeneration.
SN - 2073-4409
ER -