Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging

Abstract

SummaryGene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron-specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases.

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

“…5), provided comprehensive information on the type of altered molecules (increased or reduced) during aging. Many of these synaptic gene expression changes in layer 2/3 were also previously observed in our earlier and other reports (e.g., HOMER1, CAMKV, GFAP, CALB1, GABRA5) (Douillard-Guilloux et al, 2013; Erraji-Benchekroun et al, 2005; Lu et al, 2004; Soreq et al, 2017) suggesting that they may constitute potential markers of brain aging. Interestingly, functional analysis on differentially expressed genes/proteins of the human OFC layer 2/3 revealed a significant association with several brain disorders (Figs.…”

“…At the network level, there are age-associated alterations in neuronal communication within and between various brain regions, specifically those subserving higher-order cognitive functions, e.g., prefrontal cortex (Andrews-Hanna et al, 2007; Geerligs et al, 2015). Finally, at the molecular level, changes in gene expression patterns have been reported for neurons and glia during human aging (Erraji-Benchekroun et al, 2005; Soreq et al, 2017; Yankner et al, 2008). …”

Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide

“…This concept is complicated by the imprecise translation of characterized activation states in microglia (Hellwig et al, 2013; Mosher and Wyss-Coray, 2014). Indeed, microglial phenotypes in human neurodegenerative diseases have been difficult to characterize because of limitations in specific markers and other confounding factors such as medication usage, co-morbidities and the constantly changing dynamics of glial cells as a function of age and disease (Joers et al, 2016; Moehle and West, 2015; Soreq et al, 2017). Further, abnormal functioning of microglia in the aged or diseased brain may already have impaired restorative M2 activity (Conde and Streit, 2006; Sawada et al, 2008), leading to neurodegeneration (Luo et al, 2010).…”

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

“…Thus, microglial elimination and repopulation may be beneficial in situations that implicate altered microglial phenotypes in impaired brain function. During aging, microglia undergo marked phenotypic and functional changes compared to the adult brain, including increased cell numbers, dystrophic morphology, impaired phagocytosis, reduced motility, exaggerated response to inflammatory stimuli [reviewed in Mosher and Wyss‐Coray (2014)], as well as altered gene expression (Galatro et al, 2017; Grabert et al, 2016; Soreq, Rose, Soreq, Hardy, & Ule, 2017). These microglia are often described as “primed” or “senescent,” and recent studies suggest that these cells may contribute to age‐related cognitive impairments and confer susceptibility to neurodegenerative disease (Blank & Prinz, 2013; Niraula, Sheridan, & Godbout, 2017; Norden, Muccigrosso, & Godbout, 2015).…”