RvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome

• Published in: Glia 2020-07, Vol.68 (7), p.1347-1360
• Main Authors: Hamlett, Eric D., Hjorth, Erik, Ledreux, Aurélie, Gilmore, Anah, Schultzberg, Marianne, Granholm, Ann Charlotte
• Format: Article
• Language: English
• Subjects: Activation; Age; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Animals; cognition; Cytokines; Dementia disorders; Down syndrome; Down Syndrome - drug therapy; Down Syndrome - pathology; Down's syndrome; Eicosapentaenoic acid; Eicosapentaenoic Acid - analogs & derivatives; Eicosapentaenoic Acid - pharmacology; Hippocampus - drug effects; Hippocampus - pathology; Inflammation; Lipids; Male; Maze Learning - physiology; Memory; Memory Disorders - prevention & control; Mice, Transgenic; Neurodegeneration; Neurodegenerative diseases; neuroinflammation; Pathogenesis; Receptors; Side effects; specialized pro‐resolving mediators; Therapeutic targets; Ts65Dn
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23779

Inflammation can be resolved by pro‐homeostatic lipids called specialized pro‐resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM‐binding receptors were increased in patients with AD compared to age‐matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle‐aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro‐inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age‐matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD. A specialized pro‐resolving mediator (SPM) contributed to the resolution of inflammation in the brain of an animal model for Down syndrome. SPM activation of resolution prevented age‐related memory loss observed in Ts65Dn mice.