Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy

  • J Exp Med. 2024 Apr 1;221(4):e20232000. doi: 10.1084/jem.20232000.
Danira Toral-Rios  1 ,  Justin M Long  2  3  4 ,  Jason D Ulrich  2  3 ,  Jinsheng Yu  5 ,  Michael R Strickland  2 ,  Xianlin Han  6 ,  David M Holtzman  2  3  4 ,  Anil G Cashikar  1  2  3  7 ,  Steven M Paul  1  2  3  7
Affiliations
  • 1. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
  • 2. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
  • 3. Hope Center for Neurological Disorders, Washington University School of Medicine , St Louis, MO, USA.
  • 4. Knight Alzheimer Disease Research Center, Washington University School of Medicine , St Louis, MO, USA.
  • 5. Department of Genetics, Genome Technology Access Center at the McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
  • 6. Department of Medicine, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
  • 7. Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine , St Louis, MO, USA.
PMID: 38442267 DOI: 10.1084/jem.20232000
Abstract

Alzheimer's Disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain Lipid Metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and Lipid Metabolism, is produced by Cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.