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Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice

Abstract: Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ?-amyloid (A?) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than A? plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble A? species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, A? peptide expression and neuroinflammation). Administration of anti-IL17 for 5?months, starting at the age of 7?months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and A?1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.

 Fuente: Brain Behav Immun. 2018 Oct; 73: 235-251

Editorial: Elsevier

 Fecha de publicación: 01/10/2018

Nº de páginas: 17

Tipo de publicación: Artículo de Revista

DOI: 10.1016/j.bbi.2018.05.008

ISSN: 0889-1591,1090-2139

Proyecto español: PSI-2016-76194-R ; SAF2014-55088-R ; SAF2017-82905-R ; SAF2016-75195-R

Url de la publicación: https://doi.org/10.1016/j.bbi.2018.05.008

Autores/as

VERONICA VIDAL SANCHEZ

SUSANA GARCIA CERRO

JOSEP ORIOL NARCIS MAJOS

LLORENS MARTÍN, MARÍA

ANDREA CORRALES PARDO

SARA LANTIGUA ROMERO

IGLESIAS, MARCOS