Gladen-Kolarsky, N. | Search bioRxiv

bioRxiv2024

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

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.

neuroscience↗

bioRxiv2023

Gardenin A improves cognitive and motor function in A53T-α-syn mice

Oxidative stress and neuroinflammation are widespread in the Parkinsons disease (PD) brain and contribute to the synaptic degradation and dopaminergic cell loss that result in cognitive impairment and motor dysfunction. The polymethoxyflavone Gardenin A (GA) has been shown to activate the NRF2-regulated antioxidant pathway and inhibit the NFkB-dependent pro-inflammatory pathway in a Drosophila model of PD. Here, we evaluate the effects of GA on A53T alpha-synuclein overexpressing (A53TSyn) mice. A53TSyn mice were treated orally for 4 weeks with 0, 25, or 100 mg/kg GA. In the fourth week, mice underwent behavioral testing and tissue was harvested for immunohistochemical analysis of tyrosine hydroxylase (TH) and phosphorylated alpha synuclein (pSyn) expression, and quantification of synaptic, antioxidant and inflammatory gene expression. Results were compared to vehicle-treated C57BL6 mice. Treatment with 100 mg/kg GA improved associative memory and decreased abnormalities in mobility and gait in A53TSyn mice. GA treatment also reduced cortical and hippocampal levels of pSyn and attenuated the reduction in TH expression in the striatum. Additionally, GA increased cortical expression of NRF2-regulated antioxidant genes and decreased expression of NFkB-dependent pro-inflammatory genes. GA was readily detectable in the brains of treated mice and modulated the lipid profile in the deep gray brain tissue of those animals. While the beneficial effects of GA on cognitive deficits, motor dysfunction and PD pathology are promising, future studies are needed to further fully elucidate the mechanism of action of GA, optimizing dosing and confirm these effects in other PD models. Significance StatementThe polymethoxyflavone Gardenin A can improve cognitive and motor function and attenuate both increases in phosphorylated alpha synuclein and reductions in tyrosine hydroxylase expression in A53T alpha synuclein overexpressing mice. These effects may be related to activation of the NRF2-regulated antioxidant response and downregulation of NFkB-dependent inflammatory response by Gardenin A in treated animals. The study also showed excellent brain bioavailability of Gardenin A and modifications of the lipid profile, possibly through interactions between Gardenin A with the lipid bilayer, following oral administration. The study confirms neuroprotective activity of Gardenin A previously reported in toxin induced Drosophila model of Parkinsons disease.

neuroscience↗