The sphingosine-1-phosphate receptor functional antagonist fingolimod exacerbates neuroinflammation and tau pathology in a mouse model of tauopathy
- 1Washington University in St. Louis
Abstract
Objective: T cells are increased in the brain in Alzheimer's disease (AD) and primary tauopathies where they correlate with tau pathology. In mouse models, T cells exacerbate tau-related neuroinflammation and neurodegeneration, and depletion of T cells is neuroprotective. Here, we investigate whether the multiple sclerosis drug fingolimod may inhibit infiltration of T cells into the brain in the setting of tau pathology and thereby attenuate tau-mediated neurodegeneration. Methods: P301S-tau transgenic mice expressing human APOE4 (TE4), which develop tau pathology, neurodegeneration, and neuroinflammation with T cell accumulation, were randomly assigned to receive 1 mg/kg/d fingolimod in drinking water or standard mouse drinking water beginning just prior to the accumulation of neurofibrillary tangle pathology at 6 months of age. Mice were then assessed with a battery of cognitive behavioral assays at 9 months of age and euthanized at 9.5 months of age to analyze the blood and brain using flow cytometry, single molecule array (SIMOA) technology, stereotactic brain measurements, and immunohistochemistry. Results: Fingolimod produced the expected lymphopenia in peripheral blood but unexpectedly exacerbated brain T cell accumulation, microgliosis, astrogliosis, and tau pathology, with no significant effect on neurodegeneration or behavioral impairment in TE4 mice. Interpretation: These results indicate fundamental differences in the nature of the adaptive immune response to tau pathology versus other neuroinflammatory diseases such as multiple sclerosis and underscores the importance of understanding the impact of immune modulating therapies on all aspects of AD-related pathology in preclinical models prior to consideration and initiation of clinical trials.
Related
- Extracellular cGAMP transmission exacerbates neuroinflammation in aging and multiple sclerosis
- Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation
- Targeting the RNA regulator HuR in acute traumatic brain injury mitigates secondary injury and improves functional outcome by suppressing neuroinflammation
- Sphingosine-1-Phosphate Restrains Foamy Macrophage Formation and Modulates Inflammation in Multidrug-Resistant Tuberculosis
- 5-HT1A Antagonist WAY-100635 Prevents Chronic Neurodegeneration and Immune Activation After TBI
BibTeX
@misc{rudman2026sphingosine1phosphate,
title = {{The sphingosine-1-phosphate receptor functional antagonist fingolimod exacerbates neuroinflammation and tau pathology in a mouse model of tauopathy}},
author = {M. D. Rudman and A. Litvinchuk and C. Smith and J. Remolina Serrano and M. Manis and X. Bao and C. M. Yuede and J. D. Ulrich and D. M. Holtzman},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748583},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748583v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The sphingosine-1-phosphate receptor functional antagonist fingolimod exacerbates neuroinflammation and tau pathology in a mouse model of tauopathy
AU - M. D. Rudman
AU - A. Litvinchuk
AU - C. Smith
AU - J. Remolina Serrano
AU - M. Manis
AU - X. Bao
AU - C. M. Yuede
AU - J. D. Ulrich
AU - D. M. Holtzman
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748583
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748583v1
AB - Objective: T cells are increased in the brain in Alzheimer's disease (AD) and primary tauopathies where they correlate with tau pathology. In mouse models, T cells exacerbate tau-related neuroinflammation and neurodegeneration, and depletion of T cells is neuroprotective. Here, we investigate whether the multiple sclerosis drug fingolimod may inhibit infiltration of T cells into the brain in the setting of tau pathology and thereby attenuate tau-mediated neurodegeneration. Methods: P301S-tau transgenic mice expressing human APOE4 (TE4), which develop tau pathology, neurodegeneration, and neuroinflammation with T cell accumulation, were randomly assigned to receive 1 mg/kg/d fingolimod in drinking water or standard mouse drinking water beginning just prior to the accumulation of neurofibrillary tangle pathology at 6 months of age. Mice were then assessed with a battery of cognitive behavioral assays at 9 months of age and euthanized at 9.5 months of age to analyze the blood and brain using flow cytometry, single molecule array (SIMOA) technology, stereotactic brain measurements, and immunohistochemistry. Results: Fingolimod produced the expected lymphopenia in peripheral blood but unexpectedly exacerbated brain T cell accumulation, microgliosis, astrogliosis, and tau pathology, with no significant effect on neurodegeneration or behavioral impairment in TE4 mice. Interpretation: These results indicate fundamental differences in the nature of the adaptive immune response to tau pathology versus other neuroinflammatory diseases such as multiple sclerosis and underscores the importance of understanding the impact of immune modulating therapies on all aspects of AD-related pathology in preclinical models prior to consideration and initiation of clinical trials.
ER -