Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes

Abstract

We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN+ LLC. Some cortical NeuN+ neurons, GFAP+ glia limitans astrocytes, Iba-1+ microglia and S100β+ ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Indeed, HNE can impair lysosome function in cerebral cortical neurons, resulting in the accumulation of undegraded cargos and subsequent cell death (Zhang et al, 2017). Lipids also accumulate in autophagic vesicles (lipofuscin) or lipid-laden vesicles (Sulzer et al, 2008; Shimabukuro et al, 2016) in neurons during aging. Proteasome dysfunction and overload also occur during brain aging, which manifests as accumulations of polyubiquitinated proteins in neurons (Graham and Liu, 2017).…”

“…Within the brain, the metabolism of multiple lipid species is altered during aging as indicated by the accumulation of long-chain ceramides (Cutler et al, 2004) and lipid-laden cells (Shimabukuro et al, 2016), and a decline in brain tissue levels of omega-3 fatty acids (Denis et al, 2013). Genetic evidence also links lipid metabolism to poor brain outcomes during aging.…”

Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration

“…This indicates that similar to mammals, there are few LDs in C. elegans neurons under normal conditions. It has been reported that both aging and general obesity may increase LD accumulation in non-adipose tissues (Palikaras, Mari et al, 2017, Shimabukuro, Langhi et al, 2016, Zhou, Grayburn et al, 2000.…”

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

“…That they may have important functions in disease has recently been suggested in a drosophila model where lipid droplet formation has been reported in glia at the onset of neurodegeneration 30,31 . Oil-red-O positive "lipid-laden" cells, including neurons, astrocytes, ependymal cells and Iba1 + cells have recently been reported in mice and shown to increase with age 32 . Lipid droplets were also induced in LPS-treated mouse hippocampal slice cultures and in the N9 microglia cell line [33][34][35] .…”