The <scp>FTD</scp>‐like syndrome causing <scp>TREM</scp>2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

Kleinberger, Gernot; Brendel, Matthias; Mracskó, Éva; Wefers, Benedikt; Groeneweg, Linda; Xiang, Xianyuan; Focke, Carola; Deußing, Maximilian; Suárez‐Calvet, Marc; Mazaheri, Fargol; Parhizkar, Samira; Pettkus, Nadine; Wurst, Wolfgang; Feederle, Regina; Bartenstein, Peter; Mueggler, Thomas; Arzberger, Thomas; Knuesel, Irène; Rominger, Axel; Haass, Christian

doi:10.15252/embj.201796516

Cited by 170 publications

(200 citation statements)

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“…At least some of the GRN ‐dependent FTLD‐associated phenotypes can be mimicked in a mouse model entirely lacking PGRN (Ahmed et al , ; Yin et al , ; Wils et al , ; Gotzl et al , ). Furthermore, both, a Trem2 knockout and the knockin of the p.T66M mutation, mimic features of a FTD‐like syndrome (Kleinberger et al , ; Mazaheri et al , ). Since both proteins are preferentially expressed in microglia, we compared loss‐of‐PGRN‐associated microglial phenotypes with those known for TREM2 deficiency (Krasemann et al , ; Mazaheri et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…Signaling is terminated by proteolytic shedding of the TREM2 ectodomain (Kleinberger et al , ; Schlepckow et al , ). Several sequence variants associated with TREM2 cause neurodegeneration via a loss of function (Kleinberger et al , , ; Schlepckow et al , ; Ulland et al , ; Song et al , ). Sequence variants of TREM2 affect a multitude of functions including chemotaxis, migration, survival, binding of phospholipids and ApoE, proliferation, survival, and others (Kleinberger et al , , ; Atagi et al , ; Bailey et al , ; Wang et al , ; Yeh et al , ; Mazaheri et al , ; Ulland et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…Instead of suppressing their homeostatic mRNA signature like mouse models of neurodegenerative disorders, in the absence of TREM2 microglia even enhance expression of homeostatic genes and fail to express the disease‐associated signature (Krasemann et al , ; Mazaheri et al , ). As a result, TREM2 deficiency decreases chemotaxis, phagocytosis, and barrier function (Kleinberger et al , ; Mazaheri et al , ; Ulland et al , ). TREM2 therefore appears to play a key role as a central hub gene in the regulation of microglial homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

et al. 2019

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Microglia adopt numerous fates with homeostatic microglia ( HM ) and a microglial neurodegenerative phenotype ( MG nD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease ( AD ) and frontotemporal lobar degeneration ( FTLD ). Among these genes are progranulin ( GRN ) and the triggering receptor expressed on myeloid cells 2 ( TREM 2 ). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn −/− mice and compared their transcriptomes to those of Trem2 −/− mice . Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn −/− mice showed a reciprocal activation of the MG nD molecular signature and suppression of gene characteristic for HM . The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM 2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐ d ‐glucose)‐μ PET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

et al. 2019

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“…Interestingly, we [70] and others [71] previously found that microglial loss-of-function mutations in TREM2 affect energy metabolism throughout the entire brain. Again, a rather small percentage of brain cells seemed to influence metabolism throughout the entire brain.…”

Section: Discussionmentioning

confidence: 97%

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice

Götzl

Colombo

Fellerer

et al. 2018

Mol Neurodegeneration

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BackgroundHeterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation. We have previously reported that cathepsin (Cat) D is elevated in GRN-associated FTLD patients and Grn knockout mice. However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear.MethodsmRNA expression analysis of selected lysosomal hydrolases, lysosomal membrane proteins and autophagy-related genes was performed by NanoString nCounter panel. Protein expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts (MEF) and brains of Grn knockout mice were investigated. To selectively characterize microglial and non-microglial brain cells, an acutely isolated microglia fraction using MACS microbeads (Miltenyi Biotec) conjugated with CD11b antibody and a microglia-depleted fraction were analyzed for protein expression and maturation of selected cathepsins.ResultsWe demonstrate that loss of PGRN results in enhanced expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts and brain extracts of aged Grn knockout mice. Consistent with an overall enhanced expression and activity of lysosomal proteases in brain of Grn knockout mice, we observed an age-dependent transcriptional upregulation of certain lysosomal proteases. Thus, lysosomal dysfunction is not reflected by transcriptional downregulation of lysosomal proteases but rather by the upregulation of certain lysosomal proteases in an age-dependent manner. Surprisingly, cell specific analyses identified early lysosomal deficits in microglia before enhanced cathepsin levels could be detected in other brain cells, suggesting different functional consequences on lysosomal homeostasis in microglia and other brain cells upon lack of PGRN.ConclusionsThe present study uncovers early and selective lysosomal dysfunctions in Grn knockout microglia/macrophages. Dysregulated lysosomal homeostasis in microglia might trigger compensatory lysosomal changes in other brain cells.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0281-5) contains supplementary material, which is available to authorized users.

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“…In this issue of The EMBO Journal, Kleinberger et al (2017) provide intriguing evidence suggesting a TREM2 mutation alone can lead to striking microglial dysfunction and precipitate changes in cerebral blood flow and metabolism in mice. In this issue of The EMBO Journal, Kleinberger et al (2017) provide intriguing evidence suggesting a TREM2 mutation alone can lead to striking microglial dysfunction and precipitate changes in cerebral blood flow and metabolism in mice.…”

Section: Geneticmentioning

confidence: 98%

OH MYeloid! Immune cells wreaking havoc on brain homeostasis

Bonanno

Wyss‐Coray

2017

The EMBO Journal

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Genetic mutations responsible for neurodegenerative Nasu‐Hakola disease have been localized to the gene TREM2 and its adaptor DAP12, but it remained unclear what causes the brain to deteriorate. In this issue of The EMBO Journal, Kleinberger et al (2017) provide intriguing evidence suggesting a TREM2 mutation alone can lead to striking microglial dysfunction and precipitate changes in cerebral blood flow and metabolism in mice.

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The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

Cited by 170 publications

References 81 publications

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice

OH MYeloid! Immune cells wreaking havoc on brain homeostasis

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