Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

Abstract

While cognitive decline is observed in the normal aging monkey, neurons are not lost with age. Instead, frontal white matter is lost as myelin degenerates and both correlate with age-related cognitive decline. As age-related myelin damage increases, there should be an increase in clearance of damaged myelin by microglial phagocytosis. In this study, brains of behaviorally tested rhesus monkeys were assessed using unbiased stereology to quantify the density of activated microglia (LN3 antibody positive) and phagocytic microglia (galectin-3 (Gal-3) antibody positive) in three white matter regions: the corpus callosum, cingulum bundle (CGB), and frontal white matter (FWM). LN3 cell density was significantly increased in the CGB, whereas Gal-3 cell density was significantly increased in all regions. Increases in Gal-3 cell density in the FWM were associated with cognitive impairment. In the FWM of old animals, Gal-3-positive microglia were classified by morphological subtype as ramified, hypertrophic, or amoeboid. The densities of hypertrophic and amoeboid microglia significantly correlated with cognitive impairment. Finally, microglia were double-labeled with LN3 and Gal-3 showing that 91% of Gal-3 cells were also LN3 positive, thus expressing an Bactivated^phenotype. Furthermore, 15% of all double-labeled cells formed phagocytic cups. Overall, these results suggest that microglia become activated in white matter with age where the majority express a phagocytic phenotype. We hypothesize that age-related phagocytic activation of microglia is a response to accumulating myelin pathology. The association of Gal-3 in the FWM with cognitive impairment may reflect regional differences in damage or dysfunction of normal clearance mechanisms.

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

“…There is an increase of activated astrocytes and microglia in the white matter (Sloane et al 1999;Sloane et al 2000;Shobin et al 2017). Axons are also lost in the white matter and can be seen in the electron microscope as degenerating axons contained within degenerating myelin sheaths in keeping with the observed decrease in density of myelinated axons (Bowley et al 2010;Peters et al 2010).…”

“…This increases with age and contributes to activation of astrocytes and microglia and may exacerbate changes in myelin (Sloane et al 1999;Sloane et al 2000;Shobin et al 2017). For example, as myelin damage accumulates, oligodendrocytes try to remyelinate axons, but the resulting sheaths can be either thinner than in young adults or show abnormal redundant loops of myelin around the axons (Peters et al 2000;Peters and Sethares 2003).…”

Microglia roles in synaptic plasticity and myelination in homeostatic conditions and neurodevelopmental disorders

“…Myelination is finely and locally modified to orchestrate the timing of action potentials that may require both high and low conduction velocities (Waxman, 1997). Microglia are also involved in myelin debris clearance in normal aging (Shobin et al, 2017) and in disease conditions, as shown in cuprizone-induced demyelination models (Poliani et al, 2015;Skripuletz et al, 2010). The importance of myelin debris clearance by microglia was demonstrated by blocking microglia-specific phagocytosis through inhibition of Rab7 (a key regulator in endolysosomal trafficking (Kiral, Kohrs, Jin, & Hiesinger, 2018)).…”

Network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlPFC lead to age-related spatial working memory impairment in rhesus monkeys

“…This approach has been taken in studies of normal aging by our group and others ( reviews: Peters, 2007;Luebke et al, 2010;Wang et al, 2011;Peters and Kemper, 2012;Luebke et al, 2015), in which monkeys were assessed on working memory tasks such as the Delayed Response Task (DRT) and the Delayed Recognition Span Task in the spatial condition (DRSTsp), and their brains subsequently examined for a wide variety of parameters. Thus, declines in spatial working memory have been associated with many sub-lethal changes to the structure and function of neurons, glial cells and white matter pathways in the dlPFC of the rhesus monkey (Peters, 2007;Peters et al, 2008;Peters, 2009;Bowley et al, 2010;Luebke et al, 2010;Shobin et al, 2017). Reductions in synapses and increased dystrophy of white matter pathways begin in early middle age; for example, Peters et al (Peters et al, 2008) showed a continuous decrease in the number of excitatory and inhibitory synapses, detectable even in middle age in the monkey dlPFC.…”