Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

Md Mahiuddin Ahmed,Huntington Potter,Heidi J Chial,Christina Coughlan,Timothy D Boyd,Noah R Johnson

doi:10.3389/fnagi.2021.718426

Md Mahiuddin Ahmed, Huntington Potter + Show 4 more

Open Access

https://doi.org/10.3389/fnagi.2021.718426

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Abstract

Innate immune system activation and inflammation are associated with and may contribute to clinical outcomes in people with Down syndrome (DS), neurodegenerative diseases such as Alzheimer’s disease (AD), and normal aging. In addition to serving as potential diagnostic biomarkers, innate immune system activation and inflammation may play a contributing or causal role in these conditions, leading to the hypothesis that effective therapies should seek to dampen their effects. However, recent intervention studies with the innate immune system activator granulocyte-macrophage colony-stimulating factor (GM-CSF) in animal models of DS, AD, and normal aging, and in an AD clinical trial suggest that activating the innate immune system and inflammation may instead be therapeutic. We consider evidence that DS, AD, and normal aging are accompanied by innate immune system activation and inflammation and discuss whether and when during the disease process it may be therapeutically beneficial to suppress or promote such activation.

Highlights

Down syndrome (DS), most often caused by triplication of human chromosome 21 (Hsa21), is the most common genetic cause of both intellectual disability (ID) and age-associated cognitive decline (Epstein, 1990; Chapman and Hesketh, 2000; Silverman, 2007), affecting 1 in 700–1,000 live births worldwide (Centers for Disease Control and Prevention (CDC), 2006; Irving et al, 2008; Loane et al, 2013)
We identified granulocyte-macrophage colonystimulating factor (GM-cerebrospinal fluid (CSF)) as one such factor that is upregulated in the blood of rheumatoid arthritis (RA) patients and found that subcutaneous injection of GM-CSF for 20 days increased microglial activation, reduced amyloid pathology by more than 50%, and completely reversed the cognitive impairment of transgenic Alzheimer’s disease (AD) mice (Boyd et al, 2010), which has been replicated by other groups (Castellano et al, 2017; Kiyota et al, 2018)
The recent data indicate that targeted enhancement or inhibition of the innate immune system and inflammatory cytokines can effectively treat DS, AD, and normal aging

Summary

Introduction

Down syndrome (DS), most often caused by triplication of human chromosome 21 (Hsa21), is the most common genetic cause of both intellectual disability (ID) and age-associated cognitive decline (Epstein, 1990; Chapman and Hesketh, 2000; Silverman, 2007), affecting 1 in 700–1,000 live births worldwide (Centers for Disease Control and Prevention (CDC), 2006; Irving et al, 2008; Loane et al, 2013). Activation of astrocytes and microglia, the secretion of inflammatory cytokines (e.g., IL-1, IL-6, and TNFα), and acute phase proteins are observed in both the brains and blood of people with DS, indicating an ‘‘inflammatory endophenotype’’ (Petersen and O’Bryant, 2019).

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