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The CD74 inhibitor DRhQ improves short-term memory and mitochondrial function in 5xFAD mouse model of Aβ accumulation
Noah Gladen-Kolarsky1, Cody J Neff1, Wyatt Hack1
1Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Abstract:
Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks 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 amyloid-β (Aβ) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 µg) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. Aβ plaque burden in 5xFAD animals was not robustly impacted by DRhQ treatment in either the hippocampus or the cortex. Cortical microglial activation was similarly not apparently affected by DRhQ treatment, although in the hippocampus there was evidence of a reduction in activated microglia for 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 in AD.
Insights
DRhQ improved cognition and mitochondrial function in Alzheimer's disease (AD) mice by targeting the MIF/CD74 axis. Further studies are needed to confirm sex-specific effects on microglia and optimize treatment.
Area of Science:
- Neuroscience
- Immunology
- Mitochondrial Biology
Background:
- Neuroinflammation and mitochondrial dysfunction are key early events in Alzheimer's disease (AD).
- The macrophage migration inhibitory factor (MIF)/CD74 inflammatory axis is implicated in central nervous system (CNS) disorders, including AD.
- A novel construct, DRhQ, was developed to competitively inhibit MIF binding to CD74, modulate microglial activation, and reduce inflammation.
Purpose of the Study:
- To evaluate the therapeutic effects of DRhQ in a mouse model of Alzheimer's disease (AD).
- To assess DRhQ's impact on cognitive function, mitochondrial function, amyloid-beta (Aβ) plaque burden, and microglial activation in 5xFAD mice.
Main Methods:
- 5xFAD mice and wild-type littermates were treated with DRhQ (100 µg) or vehicle for 4 weeks.
- Cognitive performance, cortical mitochondrial function, Aβ plaque load, and microglial activation were assessed.
Main Results:
- DRhQ treatment significantly improved cognitive function and cortical mitochondrial function in both male and female 5xFAD mice.
- Aβ plaque burden in the hippocampus and cortex was not significantly affected by DRhQ.
- While cortical microglial activation remained unchanged, a reduction in activated microglia was observed in the hippocampus of female 5xFAD mice.
Conclusions:
- DRhQ demonstrates therapeutic potential for improving cognitive and mitochondrial deficits in AD.
- The findings suggest a possible sex-dependent effect of DRhQ on microglial activation in the hippocampus.
- Further research is warranted to optimize DRhQ dosage, timing, and elucidate its precise mechanism of action in AD.
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