Progranulin in the hematopoietic compartment protects mice from atherosclerosis

Nguyen, Andrew; Nguyen, Thi A.; Singh, Rajesh Kumar; Eberlé, Delphine; Zhang, Jiasheng; Abate, Jess Porter; Robles, Anatalia; Koliwad, Suneil K.; Huang, Eric J.; Maxfield, Frederick R.; Walther, Tobias C.; Farese, Robert V.

doi:10.1016/j.atherosclerosis.2018.08.042

Cited by 17 publications

(14 citation statements)

References 51 publications

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“…The finding of lipid droplet containing microglia in GRN −/− mice is corroborated by a recent study which showed that cultured progranulin-deficient macrophages exhibited increased foam cell formation, i.e. lipid droplet accumulation, compared to wild type macrophages 49 . In addition, a recent study reported that loss of GRN leads to intracellular and intra-lysosomal accumulation of long polyunsaturated triacylglyerides 50 in the brains of humans and mice.…”

Section: Discussionsupporting

confidence: 58%

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

et al. 2020

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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

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Section: Discussionsupporting

confidence: 58%

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

et al. 2020

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“…Although previously identified in aging [ 74 ] and AD [ 18 ], microglia in GRN knockout mouse models display severe accumulation of lipids, significant defects in phagocytosis, increased reactive oxygen species and elevated pro-inflammatory cytokines [ 74 ]. This extends previous research showing microglial lipofuscin accumulation [ 75 ] and foam cell formation in GRN-deficient macrophages [ 76 ] and accumulation of triacylglycerides in fibroblast and lysosomal lipidomes in humans and mice with GRN mutations [ 77 ]. Dystrophy was more severe in FTLD- C9orf72 cases in all regions compared with controls but varied considerably across cases within this group.…”

Section: Discussionsupporting

confidence: 89%

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Woollacott

Toomey

Strand

et al. 2020

J Neuroinflammation

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Background: Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer's disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls. Methods: Immunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group. Results: There was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype.

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“…The finding of lipid droplet containing microglia in GRN -/mice is corroborated by a recent study which showed that cultured progranulin-deficient macrophages exhibited increased foam cell formation, i.e. lipid droplet accumulation, compared to wild type macrophages 78 . In addition, a recent study reported that loss of GRN leads to intracellular and intra-lysosomal accumulation of long polyunsaturated triacylglyerides 79 in the brains of humans and mice.…”

Section: Lam In Neurodegenerationsupporting

confidence: 55%

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

Marschallinger

Iram

Zardeneta

et al. 2019

Preprint

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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete proinflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to agerelated and genetic forms of neurodegeneration.

show abstract

Progranulin in the hematopoietic compartment protects mice from atherosclerosis

Cited by 17 publications

References 51 publications

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

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

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

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

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