Oxidized MIF is an Alzheimer's disease drug target relaying external risk factors to tau pathology

  • Cell Rep Med. 2026 Jan 20;7(1):102520. doi: 10.1016/j.xcrm.2025.102520.
Andreas Müller-Schiffmann  1 ,  Felix Torres  2 ,  Anatoliy Kitaygorodskyy  3 ,  Anand Ramani  4 ,  Argyro Alatza  5 ,  Sarah K Tschirner  1 ,  Julien Orts  6 ,  Arthur Haltrich  1 ,  Ingrid Prikulis  1 ,  Shaofeng Yu  3 ,  Debendranath Dey  3 ,  Suguna Mallesh  3 ,  Dharma Prasad  3 ,  Dennis Solas  3 ,  Verian Bader  1 ,  Annemieke Rozemuller  7 ,  Selina Wray  5 ,  Jay Gopalakrishnan  4 ,  Roland Riek  2 ,  Vishwanath R Lingappa  3 ,  Carsten Korth  8
Affiliations
  • 1. Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 2. Laboratory of Physical Chemistry, ETH Zürich, Vladimir Prelog Weg 2, 8093 Zürich, Switzerland.
  • 3. Prosetta Biosciences Inc, 670 5th Street, San Francisco, CA 94107, USA.
  • 4. Institute of Human Genetics, University Hospital, Friedrich-Schiller-Universität Jena, 07740 Jena, Germany.
  • 5. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK.
  • 6. Laboratory of Physical Chemistry, ETH Zürich, Vladimir Prelog Weg 2, 8093 Zürich, Switzerland; Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria.
  • 7. Department Pathology, VUMC Amsterdam, 1081HV Amsterdam, the Netherlands.
  • 8. Department Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: [email protected].
PMID: 41418773 DOI: 10.1016/j.xcrm.2025.102520
Abstract

During deep co-evolution of viruses and host cells, viruses have selected specific host cellular proteins redirected from physiological functions to viral needs, thereby disturbing cellular proteostasis and increasing the risk of triggering protein misfolding diseases (PMDs). Identifying virus-specific, repurposed host proteins also allows the study of fundamental cellular events in "sporadic" PMDs, independent of the virus. Here, we identify a small molecule with very strong activity against neurotropic herpes simplex virus 1 (HSV-1), modulating an allosteric site of macrophage migration inhibitory factor (MIF). The compound efficiently reduces both HSV-1-mediated and non-mediated tau phosphorylation or aggregation in vitro and in vivo. The lead compound, as well as conformation-sensitive antibodies, specifically interacts with an oxidized conformer of MIF (oxMIF) enriched in postmortem brain homogenates of patients with Alzheimer's disease (AD). OxMIF thus participates in a host-viral interface connecting HSV-1 Infection, and possibly Other external stressors, with tau cellular pathology characteristic for PMDs, including AD.

Keywords
Alzheimer’s disease; herpes virus; macrophage migration inhibitory factor; neurodegeneration; oxMIF; protein aggregation; proteostasis; risk factor; tau; tauopathy.
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