Pre-Implantation factor (PIF) restores working memory and promotes microglial ramification in the adult Dp(16)1Yey mouse model of Down syndrome

Down syndrome (DS), the consequence of a third copy of human chromosome 21, is the most common chromosomal disorder. Several comorbidities are inconstantly associated with DS, but intellectual disability (ID) is the constant and major feature of disability. ID might be caused by several defects in neurodevelopmental processes. Among them, neuroinflammation and microglial activation have been reported in DS fetuses and children. Recent studies suggest that anti-inflammatory treatment in mouse models of DS could rescue this phenotype. The Pre-Implantation Factor (PIF) is a peptide known to have immune-modulatory, anti-inflammatory, and neuroprotective effects, and has the advantages of being physiologically secreted by the embryo and to pass the blood brain barrier. We therefore investigated the potential beneficial effect of the peptide on cognitive deficit and microglial activation, in the adult Dp (16)1Yey mouse model of DS. We showed that treatment with synthesized PIF (sPIF) in the adult Dp (16)1Yey mice improves short-term working memory and reduces microglial activation by restoring its ramification. We also showed molecular effects of sPIF treatment on microglia by lowering Iba1, Dyrk1A and EF21 levels, and by upregulating P2Y12 level. In conclusion, sPIF can rescue some aspects of cognitive deficits and modifies positively microglia morphology in a mouse model of DS.