The sphingosine-1-phosphate receptor functional antagonist fingolimod exacerbates neuroinflammation and tau pathology in a mouse model of tauopathy

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.