The CD74 inhibitor DRhQ improves cognition and mitochondrial function in 5xFAD mouse model of Aβ accumulation

Gladen-Kolarsky, N.; Neff, C. J.; Hack, W.; Brandes, M. S.; Wiedrick, J.; Meza-Romero, R.; Lockwood, D. R.; Quinn, J. F.; Offner, H.; Vandenbark, A. A.; Gray, N. E.

doi:10.1101/2024.01.29.577832

bioRxiv · 10.1101/2024.01.29.577832

The CD74 inhibitor DRhQ improves cognition and mitochondrial function in 5xFAD mouse model of Aβ accumulation

Gladen-Kolarsky, N.·Neff, C. J.·Hack, W.·Brandes, M. S.·Wiedrick, J.·Meza-Romero, R.·Lockwood, D. R.·Quinn, J. F.·Offner, H.·Vandenbark, A. A.·Gray, N. E.

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Abstract

Neuroinflammation and mitochondrial dysfunction are early events in Alzheimers disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T-cell and macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here we evaluate its effects in {beta}-amyloid (A{beta}) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 {micro}g) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. A{beta} plaque burden in 5xFAD animals were not robustly impacted by DRhQ treatment nor was microglial activation, although in the hippocampus there was some evidence of a reduction in female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation as well as to optimize the dose, and timing of DRhQ treatment and gain a better understanding of its mechanism of action.

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Gladen-Kolarsky, N., Neff, C. J., Hack, W., Brandes, M. S., Wiedrick, J., Meza-Romero, R., Lockwood, D. R., Quinn, J. F., Offner, H., Vandenbark, A. A., Gray, N. E.. 2024-01-30. The CD74 inhibitor DRhQ improves cognition and mitochondrial function in 5xFAD mouse model of Aβ accumulation. https://doi.org/10.1101/2024.01.29.577832

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