Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology
Authors
Jhodi M. Webster, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Ya-Ting Yang, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Aidan T. Miller, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Asta Zane, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Kasandra Scholz, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
William J. Stone, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Nikhita Mudium, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Nicole J. Corbin-Stein, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Woong-Jai Won, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Anna C. Stoll, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Kelsey M. Greathouse, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Noelle H. Cooper, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Lillian F. Long, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Phaedra N. Manuel, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Jeremy H. Herskowitz, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Talene A. Yacoubian, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Daniel J. Tyrrell, University of Alabama at Birmingham, Department of Pathology, Division of Molecular and Cellular Pathology, Birmingham, AL, 35294.
Ivette M. Sandoval, Barrow Neurological Institute, Department of Translational Neuroscience; Phoenix, AZ, 85013.
Fredric P. Manfredsson, Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815.
Jeffrey H. Kordower, Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815.
Ashley S. Harms, University of Alabama at Birmingham, Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, 35294.
Abstract
Alzheimer's (AD) and Parkinson disease (PD) pathology often co-occur. Amyloid-β and phosphorylated tau are found in 30-50% of idiopathic PD cases, while α-synuclein inclusions are present in 50% of AD cases. These co-pathologies are linked to increased mortality and earlier onset of cognitive decline. Immune activation is a hallmark of these neurodegenerative diseases, but current models primarily examine each pathology in isolation. How these co-pathologies drive inflammation and neuronal loss remains poorly understood. We therefore developed a mouse model combining tau, amyloid-β, and α-synuclein. We found that co-pathologies synergistically trigger an amplified neuroimmune response, with expanded populations of CD4 and CD8 tissue-resident memory T cells and CD68 microglia, compared to single pathologies. These changes were abundant in the hippocampus and cortex, regions with elevated protein pathology load and enhanced neuronal loss. Our findings demonstrate that co-pathologies enhance proteinopathy and synergistically enhance immune activation and neurodegeneration, suggesting that combinatorial therapeutic strategies that target both co-pathologies and inflammation, may be disease modifying.
Keywords
T cells, amyloid beta, co-pathologies, microglia, neuroinflammation, tau, α-synuclein
Publication Date
11-24-2025
Publication Title
bioRxiv : the preprint server for biology
Digital Object Identifier (DOI)
10.1101/2024.10.13.618101
Recommended Citation
Webster, Jhodi M.; Yang, Ya-Ting; Miller, Aidan T.; Zane, Asta; Scholz, Kasandra; Stone, William J.; Mudium, Nikhita; Corbin-Stein, Nicole J.; Won, Woong-Jai; Stoll, Anna C.; Greathouse, Kelsey M.; Cooper, Noelle H.; Long, Lillian F.; Manuel, Phaedra N.; Herskowitz, Jeremy H.; Yacoubian, Talene A.; Tyrrell, Daniel J.; Sandoval, Ivette M.; Manfredsson, Fredric P.; Kordower, Jeffrey H.; and Harms, Ashley S., "Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology" (2025). Translational Neuroscience. 2488.
https://scholar.barrowneuro.org/neurobiology/2488
