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

## TL;DR

A compound targeting oxidized MIF reduces tau pathology in Alzheimer's disease, linking external stressors like HSV-1 infection to disease progression.

## Contribution

Identifies oxidized MIF as a drug target connecting external stressors to Alzheimer's pathology and shows that small molecules can reverse tau-related effects.

## Key findings

- Oxidized MIF is enriched in the brains of Alzheimer's patients and involved in HSV-1 replication.
- PAV-174/PAV-617 inhibit tau phosphorylation and aggregation caused by oxidized MIF in vitro and in vivo.
- Oxidized MIF acts as a molecular interface linking external stressors to Alzheimer's cellular pathology.

## 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.

•HSV-1 replication involves oxMIF and can be blocked by PAV-174 inhibiting oxMIF•OxMIF, detected by a specific antibody, is enriched in brain of patients with sAD•PAV-174/ PAV-617 inhibit oxMIF-induced tau phosphorylation in vitro and in vivo independent of infection•OxMIF is a molecular interface between external stressors and cellular AD pathology

HSV-1 replication involves oxMIF and can be blocked by PAV-174 inhibiting oxMIF

OxMIF, detected by a specific antibody, is enriched in brain of patients with sAD

PAV-174/ PAV-617 inhibit oxMIF-induced tau phosphorylation in vitro and in vivo independent of infection

OxMIF is a molecular interface between external stressors and cellular AD pathology

Müller-Schiffmann et al. identify oxidized MIF as a molecular hub relaying the effects of external stressors (e.g., infection with HSV-1) to cellular pathology associated with sporadic Alzheimer’s disease. Small-molecule compound PAV-174/ PAV-617 revert oxidized MIF and contingent tau phosphorylation and aggregation independent of viral infection in vitro and in vivo.