The innate immune system stimulating cytokine GM-CSF improves learning/memory and interneuron and astrocyte brain pathology in Dp16 Down syndrome mice and improves learning/memory in wild-type mice.

Autor: Ahmed MM; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Wang AC; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Elos M; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Chial HJ; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Sillau S; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA., Solano DA; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Coughlan C; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Aghili L; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Anton P; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Markham N; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Adame V; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Gardiner KJ; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Boyd TD; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA., Potter H; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: Huntington.Potter@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2022 Jun 15; Vol. 168, pp. 105694. Date of Electronic Publication: 2022 Mar 18.
DOI: 10.1016/j.nbd.2022.105694
Abstrakt: Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the innate immune system stimulating cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which has both pro- and anti-inflammatory activities, improved cognition and reduced brain pathology in a mouse model of Alzheimer's disease (AD), another inflammatory disorder, and improved cognition and reduced biomarkers of brain pathology in a phase II trial of humans with mild-to-moderate AD. To investigate the effects of GM-CSF treatment on DS/ID in the absence of AD, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that subcutaneous GM-CSF treatment (5 μg/day, five days/week, for five weeks) improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology, increased percent area of GFAP staining in the hippocampus, clustering of astrocytes in the hippocampus, and reduced numbers of calretinin-positive interneurons in the entorhinal cortex and subiculum, and all of these brain pathologies were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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