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

Md. Mahiuddin Ahmed; Athena Ching-Jung Wang; Mihret Elos; Heidi J. Chial; Stefan Sillau; D. Adriana Solano; Christina Coughlan; Leila Aghili; Paige Anton; Neil Markham; Vanesa Adame; Katheleen J. Gardiner; Timothy D. Boyd; Huntington Potter

Neurobiology of Disease (Jun 2022)

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

Md. Mahiuddin Ahmed,
Athena Ching-Jung Wang,
Mihret Elos,
Heidi J. Chial,
Stefan Sillau,
D. Adriana Solano,
Christina Coughlan,
Leila Aghili,
Paige Anton,
Neil Markham,
Vanesa Adame,
Katheleen J. Gardiner,
Timothy D. Boyd,
Huntington Potter

Affiliations

Md. Mahiuddin Ahmed: 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
Athena Ching-Jung Wang: 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
Mihret Elos: 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
Heidi J. Chial: 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
Stefan Sillau: 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
D. Adriana Solano: 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
Christina Coughlan: 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
Leila Aghili: 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
Paige Anton: 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
Neil Markham: 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
Vanesa Adame: 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
Katheleen J. Gardiner: 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
Timothy D. Boyd: University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA
Huntington Potter: 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; Corresponding author at: Research Complex #2, Rm. 4010, Anschutz Medical Campus, University of Colorado, Denver MS 8608, 12700 E. 19th Ave., Aurora, CO 80045, USA.

Journal volume & issue: Vol. 168
p. 105694

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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