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

Area of Science:

• Virology
• Neuroscience
• Biochemistry

Background:

• Viruses hijack host proteins, disrupting cellular proteostasis and potentially causing protein misfolding diseases (PMDs).
• Studying virus-repurposed host proteins offers insights into sporadic PMDs like Alzheimer's disease (AD).

Purpose of the Study:

• To identify a small molecule targeting virus-host interactions relevant to PMDs.
• To investigate the role of macrophage migration inhibitory factor (MIF) in viral infections and tau pathology.

Main Methods:

• Screening for small molecules active against herpes simplex virus 1 (HSV-1).
• Assessing compound effects on tau phosphorylation and aggregation in vitro and in vivo.
• Utilizing conformation-sensitive antibodies to detect specific MIF conformers in postmortem brain homogenates.

Main Results:

• A potent small molecule inhibitor of HSV-1 was identified, targeting an allosteric site on MIF.
• The compound effectively reduced both HSV-1-induced and independent tau phosphorylation and aggregation.
• The lead compound and antibodies specifically interacted with an oxidized MIF conformer (oxMIF) found in Alzheimer's disease brains.

Conclusions:

• Oxidized MIF (oxMIF) acts as a host-viral interface, linking HSV-1 infection and external stressors to tau pathology in PMDs, including AD.
• This oxMIF-MIF pathway represents a potential therapeutic target for neurodegenerative diseases characterized by tau aggregation.