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Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism

Götzl, Julia K, Brendel, Matthias, Werner, Georg, Parhizkar, Samira, Sebastian Monasor, Laura, Kleinberger, Gernot, Colombo, Alessio‐Vittorio, Deussing, Maximilian, Wagner, Matias, Winkelmann, Juliane, Diehl‐Schmid, Janine, Levin, Johannes, Fellerer, Katrin, Reifschneider, Anika, Bultmann, Sebastian, Bartenstein, Peter, Rominger, Axel, Tahirovic, Sabina, Smith, Scott T, Madore, Charlotte, Butovsky, Oleg, Capell, Anja, Haass, Christian·2019·EMBO Molecular Medicine
DOI 10.15252/emmm.201809711PMC PMC6554672
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Abstract

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) 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 ( TREM2 ). 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 MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐ d ‐glucose)‐μPET 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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Figure 1 Opposite mRNA signatures of Grn −/−/Trem2 +/+ and Trem2 −/−/Grn +/+ microglia AVolcano blot representation of the differently expressed genes in FCRLS‐ and CD11b‐positive Grn −/− microglia in comparison with wt microglia isolated from 5.5‐month‐old mice (male, n = 5). 116 genes out of 529 genes analyzed are significantly changed, and from these, 58 genes are upregulated and 58 genes are downregulated. Eight up‐ and down regulated genes with the highest fold change are indicated.BHeatmap of significantly affected genes (P < 0.05) in FCRLS‐ and CD11b‐positive Grn −/− microglia in comparison with Grn +/+ microglia isolated from 5.5‐month‐old mice (n = 5 per genotype). For the significantly affected genes of the Grn −/− microglia, mRNA expression data of the Trem2 −/− microglia in comparison with the corresponding wt microglia were taken from previously published data (Mazaheri et al, 2017). The RNA counts for each gene and sample were normalized to the mean value of wt followed by a log2 transformation (n ≥ 5 per genotype). *labeled genes were not analyzed or below detection limit in Trem2 −/− microglial mRNA expression dataset (Mazaheri et al, 2017).CChanges in gene expression of 359 detected genes in Grn −/− microglia and Trem2 −/− microglia. Note that from the 38 genes significantly altered in both genotypes, 32 genes are regulated in opposite direction.DExpression levels of significantly altered homeostatic and MGnD genes of Grn −/− and Trem2 −/− microglia from the data set in (B). Gene expression is normalized to the mean of the wt cohort in comparisons with the published normalized dataset of Trem2 −/− microglia (Mazaheri et al, 2017). Data represent the mean +/− SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed between Grn −/− microglia in comparison with Grn +/+ microglia or Trem2 −/− microglia in comparison with Trem2 +/+ microglia: not significant P > 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001.
Figure 1 Opposite mRNA signatures of Grn −/−/Trem2 +/+ and Trem2 −/−/Grn +/+ microglia AVolcano blot representation of the differently expressed genes in FCRLS‐ and CD11b‐positive Grn −/− microglia in comparison with wt microglia isolated from 5.5‐month‐old mice (male, n = 5). 116 genes out of 529 genes analyzed are significantly changed, and from these, 58 genes are upregulated and 58 genes are downregulated. Eight up‐ and down regulated genes with the highest fold change are indicated.BHeatmap of significantly affected genes (P < 0.05) in FCRLS‐ and CD11b‐positive Grn −/− microglia in comparison with Grn +/+ microglia isolated from 5.5‐month‐old mice (n = 5 per genotype). For the significantly affected genes of the Grn −/− microglia, mRNA expression data of the Trem2 −/− microglia in comparison with the corresponding wt microglia were taken from previously published data (Mazaheri et al, 2017). The RNA counts for each gene and sample were normalized to the mean value of wt followed by a log2 transformation (n ≥ 5 per genotype). *labeled genes were not analyzed or below detection limit in Trem2 −/− microglial mRNA expression dataset (Mazaheri et al, 2017).CChanges in gene expression of 359 detected genes in Grn −/− microglia and Trem2 −/− microglia. Note that from the 38 genes significantly altered in both genotypes, 32 genes are regulated in opposite direction.DExpression levels of significantly altered homeostatic and MGnD genes of Grn −/− and Trem2 −/− microglia from the data set in (B). Gene expression is normalized to the mean of the wt cohort in comparisons with the published normalized dataset of Trem2 −/− microglia (Mazaheri et al, 2017). Data represent the mean +/− SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed between Grn −/− microglia in comparison with Grn +/+ microglia or Trem2 −/− microglia in comparison with Trem2 +/+ microglia: not significant P > 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001.CC BY · PubMed Central
Figure 2 Expression of microglial marker protein characteristic for the homeostatic or disease‐associated state AImmunoblot analysis of ApoE, CLEC7A, TREM2, and CD68 in lysates of acutely isolated microglia from Grn −/− and Grn +/+ mice (9 months of age, n = 3 per genotype, female). IBA1 was used as loading control. The asterisk indicates an unspecific band.BQuantification of protein expression normalized to levels of Grn +/+ microglia (n = 3). Data represent the mean ± SD.CELISA‐mediated quantification of sTREM2 in brain homogenates of Grn −/− and Grn +/+ mice. Data are shown as mean ± SEM (n = 3–6).DELISA‐mediated quantification of sTREM2 in serum of Grn −/− and Grn +/+ mice. Data are shown as mean ± SEM (n = 4–13).EMicroglial expression of P2RY12 in cortical sections of wt, Grn −/− and Trem2 −/− mice. (9 months of age, female). Scale bar indicates 10 μm.FQuantification of P2RY12‐positive microglia. Data are shown as mean ± SD (n = 3 per genotype, female, except one male for Trem2 −/−).GImmunoblot analysis of secreted PGRN and ApoE (ApoEmed) in conditioned media and PGRN, ApoE, CLEC7A, P2RY12, and TREM2 in lysates of BV2 wild‐type (Grn wt) and PGRN‐deficient (Grn mut) cells. Soluble amyloid precursor protein (APPs) and calnexin were used as a loading control. The asterisk indicates an unspecific band.HQuantification of immunoblots normalized to BV2 Grn wt levels (n = 3–5). Data represent the mean ± SD.IELISA‐mediated quantification of sTREM2 in conditioned media of BV2 Grn wt and Grn mut cells. Data represent the mean ± SD (n = 4).JQuantification of relative mRNA levels of Apoe, Clec7a, P2ry12, and Trem2 in BV2 Grn wt and Grn mut cells. Data represent the mean ± SD (n = 3).Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed between Grn mut or Grn −/− in comparison with Grn wt or Grn +/+: n.s., not significant; *P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001. For (F), the one‐way ANOVA with Tukey post hoc test was used.Source data are available online for this figure.
Figure 2 Expression of microglial marker protein characteristic for the homeostatic or disease‐associated state AImmunoblot analysis of ApoE, CLEC7A, TREM2, and CD68 in lysates of acutely isolated microglia from Grn −/− and Grn +/+ mice (9 months of age, n = 3 per genotype, female). IBA1 was used as loading control. The asterisk indicates an unspecific band.BQuantification of protein expression normalized to levels of Grn +/+ microglia (n = 3). Data represent the mean ± SD.CELISA‐mediated quantification of sTREM2 in brain homogenates of Grn −/− and Grn +/+ mice. Data are shown as mean ± SEM (n = 3–6).DELISA‐mediated quantification of sTREM2 in serum of Grn −/− and Grn +/+ mice. Data are shown as mean ± SEM (n = 4–13).EMicroglial expression of P2RY12 in cortical sections of wt, Grn −/− and Trem2 −/− mice. (9 months of age, female). Scale bar indicates 10 μm.FQuantification of P2RY12‐positive microglia. Data are shown as mean ± SD (n = 3 per genotype, female, except one male for Trem2 −/−).GImmunoblot analysis of secreted PGRN and ApoE (ApoEmed) in conditioned media and PGRN, ApoE, CLEC7A, P2RY12, and TREM2 in lysates of BV2 wild‐type (Grn wt) and PGRN‐deficient (Grn mut) cells. Soluble amyloid precursor protein (APPs) and calnexin were used as a loading control. The asterisk indicates an unspecific band.HQuantification of immunoblots normalized to BV2 Grn wt levels (n = 3–5). Data represent the mean ± SD.IELISA‐mediated quantification of sTREM2 in conditioned media of BV2 Grn wt and Grn mut cells. Data represent the mean ± SD (n = 4).JQuantification of relative mRNA levels of Apoe, Clec7a, P2ry12, and Trem2 in BV2 Grn wt and Grn mut cells. Data represent the mean ± SD (n = 3).Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed between Grn mut or Grn −/− in comparison with Grn wt or Grn +/+: n.s., not significant; *P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001. For (F), the one‐way ANOVA with Tukey post hoc test was used.Source data are available online for this figure.CC BY · PubMed Central
Figure 3 Enhanced phagocytosis, migration, and clustering around amyloid plaques upon PGRN deficiency AFlow cytometric analysis of phagocytic capacity in BV2wt and BV2mut cells using pHrodo green E. coli as target particles. Phagocytosis was terminated after 30 and 60 min (min) of incubation. Data are presented as mean percentage of cells positive for pHrodo uptake ± SD (n = 3).BEnhanced migration of CD68‐positive, PGRN‐deficient cells in an ex vivo model. Immunofluorescence analysis of cultured Grn +/+ and Grn −/− organotypic brain at 7 DIV immunostained using microglial marker CD68. Nuclei were counterstained using DAPI. Images of boxed regions in left panels are shown at higher magnifications in right panels. Scale bars: 500 μm (left panels), 250 μm (right panels).CQuantitative analysis reveals that Grn −/− microglia migrate larger distances than Grn +/+. Data are shown as mean ± SD (n = 3 independent experiments).DQuantification displays an increased number of migrating Grn −/− cells compared to Grn +/+ cells. Data are shown as mean ± SD (n = 3 independent experiments).EEnhanced microglial clustering around amyloid plaques in the absence of PGRN. Left: IBA1‐stained microglial clustering around X‐34‐positive amyloid plaque cores in 4‐month‐old APPPS1/Grn +/+ mice. Right: Age‐matched APPPS1/Grn −/− mice display microglial hyper‐clustering around amyloid plaques compared with APPPS1/Grn +/+. Dotted white boxes indicate the area that is shown at higher magnification. Scale bars indicate 10 and 3 μm in inset.FImmunohistochemical quantification of IBA1‐positive microglial cell number per plaque (APPPS1/Grn +/+ n = 4, APPPS1/Grn −/− n = 4; 4‐month‐old; two males and two females per genotype) normalized to APPPS1/Grn +/+ mice. Approximately 20–50 amyloid plaques were counted per mouse in 3 cortical sections to calculate the number of IBA1‐positive microglia per plaque. Data are shown as mean ± SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed (A, C, D) between PGRN‐deficient Grnmut BV2 cells or Grn −/− microglia and Grn wt BV2 cells or Grn +/+ microglia. For (F) the Mann–Whitney U‐test, two‐tailed analysis was used. Significance is indicated by *P < 0.05; **P < 0.01; and ***P < 0.001.Source data are available online for this figure.
Figure 3 Enhanced phagocytosis, migration, and clustering around amyloid plaques upon PGRN deficiency AFlow cytometric analysis of phagocytic capacity in BV2wt and BV2mut cells using pHrodo green E. coli as target particles. Phagocytosis was terminated after 30 and 60 min (min) of incubation. Data are presented as mean percentage of cells positive for pHrodo uptake ± SD (n = 3).BEnhanced migration of CD68‐positive, PGRN‐deficient cells in an ex vivo model. Immunofluorescence analysis of cultured Grn +/+ and Grn −/− organotypic brain at 7 DIV immunostained using microglial marker CD68. Nuclei were counterstained using DAPI. Images of boxed regions in left panels are shown at higher magnifications in right panels. Scale bars: 500 μm (left panels), 250 μm (right panels).CQuantitative analysis reveals that Grn −/− microglia migrate larger distances than Grn +/+. Data are shown as mean ± SD (n = 3 independent experiments).DQuantification displays an increased number of migrating Grn −/− cells compared to Grn +/+ cells. Data are shown as mean ± SD (n = 3 independent experiments).EEnhanced microglial clustering around amyloid plaques in the absence of PGRN. Left: IBA1‐stained microglial clustering around X‐34‐positive amyloid plaque cores in 4‐month‐old APPPS1/Grn +/+ mice. Right: Age‐matched APPPS1/Grn −/− mice display microglial hyper‐clustering around amyloid plaques compared with APPPS1/Grn +/+. Dotted white boxes indicate the area that is shown at higher magnification. Scale bars indicate 10 and 3 μm in inset.FImmunohistochemical quantification of IBA1‐positive microglial cell number per plaque (APPPS1/Grn +/+ n = 4, APPPS1/Grn −/− n = 4; 4‐month‐old; two males and two females per genotype) normalized to APPPS1/Grn +/+ mice. Approximately 20–50 amyloid plaques were counted per mouse in 3 cortical sections to calculate the number of IBA1‐positive microglia per plaque. Data are shown as mean ± SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed (A, C, D) between PGRN‐deficient Grnmut BV2 cells or Grn −/− microglia and Grn wt BV2 cells or Grn +/+ microglia. For (F) the Mann–Whitney U‐test, two‐tailed analysis was used. Significance is indicated by *P < 0.05; **P < 0.01; and ***P < 0.001.Source data are available online for this figure.CC BY · PubMed Central
Figure EV1 Reduced phagocytosis upon TREM2 deficiency in contrast to enhanced phagocytosis and clustering around amyloid plaques in the absence of PGRN AFlow cytometric analysis of phagocytic capacity in N9 Trem2 wt and N9 Trem2 mut cells using pHrodo green E. coli as target particles. Phagocytosis was terminated after 45 min of incubation. Data are presented as mean percentage of cells positive for pHrodo uptake ± SD (n = 3).BFlow cytometric analysis of phagocytic capacity of cultured primary microglia from wild‐type, Grn −/−, and Trem2 −/− mice (2 months of age, male) using pHrodo green E. coli as target particles. Phagocytosis was terminated after 45 min of incubation. Left panel: Data are presented as mean percentage of CD11b+ cells positive for pHrodo uptake ± SD (three biological replicates). Right panel: Data are presented as mean percentage of CD11b+ cells positive for pHrodo uptake ± SD (two biological replicates).CPercentage IBA1‐positive microglia within given plaque distance quantified from immunohistochemical stainings shown in Fig 3E. Data are normalized to APPPS1/Grn +/+ mice (n = 4; 4‐month‐old; two males and two females per genotype). Data are shown as mean ± SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed (A, B) between TREM2 or PGRN‐deficient microglia against wild‐type microglia, and the Mann–Whitney U‐test, two‐tailed analysis (C) was performed between genotypes. Significance is indicated by *P < 0.05.Source data are available online for this figure.
Figure EV1 Reduced phagocytosis upon TREM2 deficiency in contrast to enhanced phagocytosis and clustering around amyloid plaques in the absence of PGRN AFlow cytometric analysis of phagocytic capacity in N9 Trem2 wt and N9 Trem2 mut cells using pHrodo green E. coli as target particles. Phagocytosis was terminated after 45 min of incubation. Data are presented as mean percentage of cells positive for pHrodo uptake ± SD (n = 3).BFlow cytometric analysis of phagocytic capacity of cultured primary microglia from wild‐type, Grn −/−, and Trem2 −/− mice (2 months of age, male) using pHrodo green E. coli as target particles. Phagocytosis was terminated after 45 min of incubation. Left panel: Data are presented as mean percentage of CD11b+ cells positive for pHrodo uptake ± SD (three biological replicates). Right panel: Data are presented as mean percentage of CD11b+ cells positive for pHrodo uptake ± SD (two biological replicates).CPercentage IBA1‐positive microglia within given plaque distance quantified from immunohistochemical stainings shown in Fig 3E. Data are normalized to APPPS1/Grn +/+ mice (n = 4; 4‐month‐old; two males and two females per genotype). Data are shown as mean ± SD.Data information: For statistical analysis, unpaired two‐tailed Student's t‐test was performed (A, B) between TREM2 or PGRN‐deficient microglia against wild‐type microglia, and the Mann–Whitney U‐test, two‐tailed analysis (C) was performed between genotypes. Significance is indicated by *P < 0.05.Source data are available online for this figure.CC BY · PubMed Central
Figure 4 Enhanced microglial activity in Grn −/− mice and in a patient with Grn haploinsufficiency ATSPO‐μPET in rodents: Axial slices (A1, A2, A3) of averaged %‐TSPO‐PET differences between Grn −/− or Trem2 −/− mice and wt indicate increased microglial activity in the cerebrum of Grn −/− mice (hot color scale) and decreased microglial activity in the cerebrum of Trem2 −/− mice (cold color scale). Scatter plot depicts single TSPO‐μPET values deriving from a neocortical volume of interest. Data represent the mean +/− SD. μPET results are illustrated upon an MRI template; 6–10 female mice per group (Grn −/− n = 6 at 8 months, Trem2 −/− n = 8 at 11 months; wt n = 10 at 8–11 months). Statistics were derived from one‐way ANOVA with Tukey post hoc test.BPGRN serum levels of the patients subjected to TSPO‐PET confirmed the GRN mutation and non‐GRN mutation carrier. PGRN was measured by ELISA in technical triplicates and normalized to serum levels of a healthy control. Data represent the mean +/− SD.CTSPO‐PET in human FTLD patients: Visual interpretation of axial TSPO‐PET SUVR images in upper cranial layers reveals increased microglial activity in frontal and parietal cortices (white arrows) of a FTLD patient with a GRN loss‐of‐function mutation in comparison with a FTLD patient without a GRN mutation. PET results are illustrated upon an MRI template; 60–80 min p.i. emission recording; and global mean scaling. Both patients were low‐affinity binder.
Figure 4 Enhanced microglial activity in Grn −/− mice and in a patient with Grn haploinsufficiency ATSPO‐μPET in rodents: Axial slices (A1, A2, A3) of averaged %‐TSPO‐PET differences between Grn −/− or Trem2 −/− mice and wt indicate increased microglial activity in the cerebrum of Grn −/− mice (hot color scale) and decreased microglial activity in the cerebrum of Trem2 −/− mice (cold color scale). Scatter plot depicts single TSPO‐μPET values deriving from a neocortical volume of interest. Data represent the mean +/− SD. μPET results are illustrated upon an MRI template; 6–10 female mice per group (Grn −/− n = 6 at 8 months, Trem2 −/− n = 8 at 11 months; wt n = 10 at 8–11 months). Statistics were derived from one‐way ANOVA with Tukey post hoc test.BPGRN serum levels of the patients subjected to TSPO‐PET confirmed the GRN mutation and non‐GRN mutation carrier. PGRN was measured by ELISA in technical triplicates and normalized to serum levels of a healthy control. Data represent the mean +/− SD.CTSPO‐PET in human FTLD patients: Visual interpretation of axial TSPO‐PET SUVR images in upper cranial layers reveals increased microglial activity in frontal and parietal cortices (white arrows) of a FTLD patient with a GRN loss‐of‐function mutation in comparison with a FTLD patient without a GRN mutation. PET results are illustrated upon an MRI template; 60–80 min p.i. emission recording; and global mean scaling. Both patients were low‐affinity binder.CC BY · PubMed Central
Figure 5 Cerebral hypometabolism upon loss of GRN and TREM2 FDG‐μPET in rodents: Axial slices (as indicated in Fig 4A) of averaged %‐FDG‐μPET differences between Grn −/− or Trem2 −/− mice and wt indicate decreased glucose metabolism in the cerebrum of Grn −/− and Trem2 −/− (both cold color scales) when compared to wt. Scatter plot depicts single FDG‐PET values deriving from a neocortical volume of interest. Data represent the mean +/− SD. μPET results are illustrated upon an MRI template; 6–10 female mice per group (Grn −/− n = 6 at 8 months, Trem2 −/− n = 6 at 11 months; wt n = 10 at 8–11 months). Statistics were derived from one‐way ANOVA with Tukey post hoc test.
Figure 5 Cerebral hypometabolism upon loss of GRN and TREM2 FDG‐μPET in rodents: Axial slices (as indicated in Fig 4A) of averaged %‐FDG‐μPET differences between Grn −/− or Trem2 −/− mice and wt indicate decreased glucose metabolism in the cerebrum of Grn −/− and Trem2 −/− (both cold color scales) when compared to wt. Scatter plot depicts single FDG‐PET values deriving from a neocortical volume of interest. Data represent the mean +/− SD. μPET results are illustrated upon an MRI template; 6–10 female mice per group (Grn −/− n = 6 at 8 months, Trem2 −/− n = 6 at 11 months; wt n = 10 at 8–11 months). Statistics were derived from one‐way ANOVA with Tukey post hoc test.CC BY · PubMed Central
Figure 6 Modulation of microglia activity states within a narrow therapeutic window Schematic presentation of the disease‐associated/homeostatic phenotypes observed in Grn −/− mice versus Trem2 −/− and the potential consequences for a therapeutic window of microglial modulation.
Figure 6 Modulation of microglia activity states within a narrow therapeutic window Schematic presentation of the disease‐associated/homeostatic phenotypes observed in Grn −/− mice versus Trem2 −/− and the potential consequences for a therapeutic window of microglial modulation.CC BY · PubMed Central

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Research works printed but not linked: 39

  1. Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S et al (2010) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 177: 311–324 · DOI
  2. Albert NL, Unterrainer M, Fleischmann DF, Lindner S, Vettermann F, Brunegraf A, Vomacka L, Brendel M, Wenter V, Wetzel C et al (2017) TSPO PET for glioma imaging using the novel ligand (18)F‐GE‐180: first results in patients with glioblastoma. Eur J Nucl Med Mol Imaging 44: 2230–2238 · DOI
  3. Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S (1990) Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 173: 1161–1168 · DOI
  4. Beel S, Moisse M, Damme M, De Muynck L, Robberecht W, Van Den Bosch L, Saftig P, Van Damme P (2017) Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo. Hum Mol Genet 26: 2850–2863 · DOI · Paper page
  5. Belcourt DR, Lazure C, Bennett HP (1993) Isolation and primary structure of the three major forms of granulin‐like peptides from hematopoietic tissues of a teleost fish (Cyprinus carpio). J Biol Chem 268: 9230–9237 · DOI
  6. Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31: 616–621 · DOI
  7. Borroni B, Ferrari F, Galimberti D, Nacmias B, Barone C, Bagnoli S, Fenoglio C, Piaceri I, Archetti S, Bonvicini C et al (2014) Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging 35: 934 e937–910 · DOI · Paper page
  8. Brendel M, Probst F, Jaworska A, Overhoff F, Korzhova V, Albert NL, Beck R, Lindner S, Gildehaus FJ, Baumann K et al (2016) Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple‐tracer PET study. J Nucl Med 57: 954–960 · DOI
  9. Capell A, Liebscher S, Fellerer K, Brouwers N, Willem M, Lammich S, Gijselinck I, Bittner T, Carlson AM, Sasse F et al (2011) Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci 31: 1885–1894 · DOI
  10. Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G (2012) Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 287: 32298–32306 · DOI
  11. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, Sheng M (2017) Progranulin deficiency causes impairment of autophagy and TDP‐43 accumulation. J Exp Med 214: 2611–2628 · DOI · Paper page
  12. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ et al (2006) Null mutations in progranulin cause ubiquitin‐positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920–924 · DOI · Paper page
  13. Cruts M, Van Broeckhoven C (2008) Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 24: 186–194 · DOI
  14. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N et al (2014) Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging 35: 726 e711–729 · DOI
  15. Deussing M, Blume T, Vomacka L, Mahler C, Focke C, Todica A, Unterrainer M, Albert NL, Lindner S, von Ungern‐Sternberg B et al (2017) Coupling between physiological TSPO expression in brain and myocardium allows stabilization of late‐phase cerebral [(18)F]GE180 PET quantification. NeuroImage 165: 83–91 · DOI
  16. Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, van der Zee J, Lang CM, Kremmer E et al (2014) Common pathobiochemical hallmarks of progranulin‐associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127: 845–860
  17. Gotzl JK, Lang CM, Haass C, Capell A (2016) Impaired protein degradation in FTLD and related disorders. Ageing Res Rev 32: 122–139 · DOI
  18. Gotzl JK, Colombo AV, Fellerer K, Reifschneider A, Werner G, Tahirovic S, Haass C, Capell A (2018) Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice. Mol Neurodegener 13: 48 · DOI
  19. Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin‐mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68: 654–667 · DOI · Paper page
  20. Jonsson T, Stefansson K (2013) TREM2 and neurodegenerative disease. N Engl J Med 369: 1568–1569
  21. Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K, Kotaki H, Horai R, Iwakura Y, Nishihara M (2007) Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 185: 110–118 · DOI
  22. Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deussing M, Suarez‐Calvet M, Mazaheri F et al (2017) The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J 36: 1837–1853 · DOI
  23. Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ et al (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin‐induced injury. J Clin Invest 122: 3955–3959 · DOI
  24. Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I, De Luca V, Wilson AA, Houle S (2012) Translocator protein (18 kDa) polymorphism (rs6971) explains in‐vivo brain binding affinity of the PET radioligand [(18)F]‐FEPPA. J Cereb Blood Flow Metab 32: 968–972 · DOI · Paper page
  25. Overhoff F, Brendel M, Jaworska A, Korzhova V, Delker A, Probst F, Focke C, Gildehaus FJ, Carlsen J, Baumann K et al (2016) Automated spatial brain normalization and hindbrain white matter reference tissue give improved [(18)F]‐florbetaben pet quantitation in Alzheimer's model mice. Front Neurosci 10: 45 · DOI
  26. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA et al (2012) An 18‐kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32: 1–5 · DOI · Paper page
  27. Rominger A, Brendel M, Burgold S, Keppler K, Baumann K, Xiong G, Mille E, Gildehaus FJ, Carlsen J, Schlichtiger J et al (2013) Longitudinal assessment of cerebral beta‐amyloid deposition in mice overexpressing Swedish mutant beta‐amyloid precursor protein using 18F‐florbetaben PET. J Nucl Med 54: 1127–1134 · DOI
  28. Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C (2017) An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med 9: 1356–1365 · DOI
  29. Shoyab M, McDonald VL, Byles C, Todaro GJ, Plowman GD (1990) Epithelins 1 and 2: isolation and characterization of two cysteine‐rich growth‐modulating proteins. Proc Natl Acad Sci USA 87: 7912–7916 · DOI
  30. Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM, Alzheimer's Disease Neuroimaging I (2017) Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol 133: 785–807 · DOI
  31. Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M (2013a) Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin‐deficient mice. Neuroscience 231: 49–60 · DOI
  32. Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M (2013b) Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin‐deficient mice. Neuroscience 250: 8–19 · DOI
  33. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, Hernandez M, Colonna M (2006) Cutting edge: TREM‐2 attenuates macrophage activation. J Immunol 177: 3520–3524 · DOI · Paper page
  34. Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, van Swieten J, Carmeliet P, Van Den Bosch L, Robberecht W (2008) Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181: 37–41 · DOI
  35. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160: 1061–1071 · DOI · Paper page
  36. Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C et al (2012) Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice. J Pathol 228: 67–76 · DOI
  37. Zhang N, Yang N, Chen Q, Qiu F, Li X (2014) Upregulated expression level of the growth factor, progranulin, is associated with the development of primary Sjogren's syndrome. Exp Ther Med 8: 1643–1647 · DOI
  38. Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F (2015) Prosaposin facilitates sortilin‐independent lysosomal trafficking of progranulin. J Cell Biol 210: 991–1002 · DOI
  39. Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JCC, Nishimura N, Seeley WW et al (2017) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8: 15277 · DOI

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Metadata

Authors
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Sebastian Monasor, L., Kleinberger, G., Colombo, A., Deussing, M., Wagner, M., Winkelmann, J., Diehl‐Schmid, J., Levin, J., Fellerer, K., Reifschneider, A., Bultmann, S., Bartenstein, P., Rominger, A., Tahirovic, S., Smith, S. T., Madore, C., Butovsky, O., Capell, A., & Haass, C.
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-05-23
Volume
11
Issue
6
ISSN
  • 1757-4676
  • 1757-4684
DOI
10.15252/emmm.201809711
PMC
PMC6554672
Cited by
118
References
36
Language
en
Licence
Funders
  • HHS|NIH|National Institute of Neurological Disorders and Stroke (R01 NS088137, R21NS104609, R21NS101673)
  • Nancy Davis Foundation for Multiple Sclerosis Faculty Award
  • Cure Alzheimer's Fund
  • Amyotrophic Lateral Sclerosis Association
  • Hans and Ilse Breuer Foundation
  • Bundesministerium für Bildung und Forschung (FTLDc 01GI1007A)
  • HHS|National Institutes of Health (NEY (R01 EY027921))
  • HHS|NIH|National Institute on Aging (R01 AG051812, R01 AG054672)
  • Deutsche Forschungsgemeinschaft (EXC 1010 SyNergy, HA1737/16‐1, BR4580/1‐1, RO5194/1‐1)
  • NOMIS Foundation
  • National Multiple Sclerosis Society (5092A1)
  • Sanofi

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