Abstract
To date, microglia subsets in the healthy CNS have not been identified. Utilizing autofluorescence (AF) as a discriminating parameter, we identified two novel microglia subsets in both mice and non-human primates, termed autofluorescence-positive (AF+) and negative (AF-). While their proportion remained constant throughout most adult life, the AF signal linearly and specifically increased in AF+ microglia with age and correlated with a commensurate increase in size and complexity of lysosomal storage bodies, as detected by transmission electron microscopy and LAMP1 levels. Post-depletion repopulation kinetics revealed AF- cells as likely precursors of AF+ microglia. At the molecular level, the proteome of AF+ microglia showed overrepresentation of endolysosomal, autophagic, catabolic, and mTOR-related proteins. Mimicking the effect of advanced aging, genetic disruption of lysosomal function accelerated the accumulation of storage bodies in AF+ cells and led to impaired microglia physiology and cell death, suggestive of a mechanistic convergence between aging and lysosomal storage disorders.
Highlights
Microglia are a unique population of tissue resident macrophages residing in the central nervous system (CNS) accounting for 10% to 15% of all cells within the CNS
Given the abundance of intracellular storage bodies and the increased detection of proteins involved in endocytosis and phagosome maturation observed in AF+ microglia, we investigated whether differential phagocytosis of myelin debris contributed to the subset-specific accumulation of AF storage material
To explore whether other phagocytic activities were contributors to AF accumulation, we examined Fc-receptor mediated and Triggering Receptor Expressed on Myeloid cells 2 (TREM2)-mediated phagocytosis using Fcer1g / mice, which lack the common Fc-gamma chain required for functional expression of activating Fc-receptors (Takai et al, 1994), and Trem2 / mice, which were reported to have microglia defective in the engulfment of apoptotic neurons, myelin debris, and synapses (Cantoni et al, 2015; Hsieh et al, 2009; Wang et al, 2015)
Summary
Microglia are a unique population of tissue resident macrophages residing in the central nervous system (CNS) accounting for 10% to 15% of all cells within the CNS. While displaying some canonical macrophage activities such as the phagocytosis of debris and apoptotic bodies (Chan et al, 2001; Janda et al, 2018), microglia are endowed with functions specific to the CNS microenvironment (Clayton et al, 2017; Li and Barres, 2018; Ransohoff, 2016; Ransohoff and Khoury, 2016), such as synaptic remodeling (Paolicelli et al, 2011; Stephan et al, 2012; Stevens et al, 2007; Weinhard et al, 2018), neuronal support (Parkhurst et al, 2013; Ueno et al, 2013), and oligodendrogenesis (Hagemeyer et al, 2017; Wlodarczyk et al, 2017) Despite this diversity of functions, no durable subsets have been identified in the healthy adult brain at steady-state. AF+ and AF microglia differed in their ultrastructural features, homeostatic dynamics, proteomic content and physiological properties
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