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Aims Cerebral ischemia can lead to anxiety and cognitive impairment due to the loss of hippocampal neurons. Facilitation of endogenous neurogenesis in the hippocampus is a potential therapeutic strategy for alleviating ischemia‐induced anxiety and cognitive impairment. Progranulin (PGRN), a secretory glycoprotein, has been reported to have a mitogentic effect on many cell types. However, it is not clear whether PGRN enhances hippocampal neurogenesis and promotes functional recovery. Methods Adult male C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and injected intracerebroventricularly with recombinant mouse PGRN 30 min after pMCAO. Anxiety‐like behavior was detected by the open field and the elevated plus maze tests, and spatial learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double labeling of BrdU and neural stem cells or neurons markers. For mechanism studies, the level of ERK1/2 and AKT phosphorylation were assessed by western blotting. Results Progranulin significantly alleviated anxiety‐like behavior and spatial learning and memory impairment induced by cerebral ischemia in mice. Consistent with the functional recovery, PGRN promoted neural stem cells (NSCs) proliferation and neuronal differentiation in the dentate gyrus (DG) after cerebral ischemia. PGRN upregulated the expression of phosphorylated ERK1/2 and Akt in the DG after cerebral ischemia. Conclusions Progranulin alleviates ischemia‐induced anxiety‐like behavior and spatial learning and memory impairment in mice, probably via stimulation of hippocampal neurogenesis mediated by activation of MAPK/ERK and PI3K/Akt pathways. PGRN might be a promising candidate for coping with ischemic stroke‐induced mood and cognitive impairment in clinic. Progranulin alleviates anxiety‐like behavior and spatial learning and memory impairment induced by cerebral ischemia, which is due to stimulating hippocampal neurogenesis through activation of MAPK/ERK and PI3K/Akt signaling pathways.

Background Chronic kidney disease (CKD) is a prevalent global health issue characterized by progressive renal dysfunction and fibrosis, often leading to end-stage renal failure. Renal fibrosis, a hallmark of CKD, is driven by complex immune responses, including macrophage polarization and inflammatory signaling pathways. Progranulin (PGRN), a glycoprotein involved in inflammation and tissue repair, has emerged as a key regulator in various fibrotic diseases. However, the precise role of PGRN in macrophage polarization and renal fibrosis in CKD remains unclear and warrants further investigation. Methods Renal tissue samples from CKD patients and unilateral ureteral obstruction (UUO)-induced mice were analyzed using immunohistochemistry, immunofluorescence, Western blotting, and qRT-PCR to assess fibrosis, macrophage infiltration, and key markers of autophagy and inflammation. Recombinant PGRN (rPGRN) was administered in vivo to assess its effects on renal fibrosis, macrophage polarization, and autophagic flux. To evaluate the role of PGRN, PGRN knockout (PGRN −/− ) mice were also utilized. The effects of PGRN on autophagic flux and mitochondrial dynamics were studied using mCherry-GFP-LC3 dual-labeling, and macrophage polarization was analyzed by flow cytometry and cytokine profiling. Results PGRN expression is significantly elevated in CKD patients and UUO mice and is associated with increased macrophage infiltration and renal fibrosis. rPGRN administration in vivo aggravated fibrosis and promoted M2 macrophage polarization. In contrast, PGRN −/− mice showed reduced renal fibrosis, significantly reduced collagen deposition, and reduced expression of pro-fibrotic cytokines. In addition, the mitochondrial function of PGRN −/− renal fibrosis mice was improved, the mtDNA content of mouse kidney tissue was increased, the results of electron microscopy showed that the mitochondrial structure was relatively normal, the mitochondrial biogenesis related genes PGC1α, TOMM20 and Fis1 were up-regulated, and the levels of MFN2 and Drp1 were significantly reduced. In addition, autophagy related gene LC3 was decreased and P62 protein level was increased in PGRN −/− model mice. Mechanically, PGRN interacts with autophagy related proteins ATG5 and ATG12 to regulate autophagy flux through the PI3K-Akt signaling pathway and promote the polarization of M2 macrophages. Conclusion PGRN plays a critical role in driving renal fibrosis by regulating macrophage polarization, autophagy, and mitochondrial dynamics. Our findings suggest that PGRN exacerbates CKD progression by promoting M2 macrophage polarization and disrupting autophagic processes, highlighting PGRN as a potential therapeutic target for the treatment of CKD and renal fibrosis.

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease. Synopsis Neuroinflammation and microgliosis are key pathological features of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) protein levels analysis in large AD patients' cohorts reveals that CSF levels of Progranulin (PGRN) together with soluble TREM2 may serve as a microglia activity marker in AD. CSF PGRN increases in carriers of autosomal‐dominant AD from the Dominant Inherited Alzheimer's Disease Network (DIAN), causing dominant mutations 10 years before the expected symptom onset. CSF PGRN increases in late‐onset AD patients from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort during the course of the disease and is associated with cognitive decline. CSF PGRN and CSF soluble TREM2 (sTREM2), both of which have key regulatory functions in microglia, are associated specifically when there is underlying neurodegeneration. CSF PGRN together with CSF sTREM2 may serve as microglial activity markers and could be used to prove target engagement in clinical trials aiming to modulate microglial activity. Graphical Abstract Neuroinflammation and microgliosis are key pathological features of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) protein levels analysis in large AD patients' cohorts reveals that CSF levels of Progranulin (PGRN) together with soluble TREM2 may serve as a microglia activity marker in AD.

Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Progranulin (PGRN), which is produced in neurons and microglia, is a neurotrophic and anti-inflammatory glycoprotein. Human loss-of-function mutations cause frontotemporal dementia, and PGRN knockout (KO) mice are a model for dementia. In addition, PGRN KO mice exhibit severe phenotypes in models of traumatic or ischemic central nervous system (CNS) disorders, including traumatic brain injury (TBI). It is unknown whether restoration of progranulin expression in neurons (and not in microglia) might be sufficient to prevent excessive TBI-evoked brain damage. To address this question, we generated mice with Nestin-Cre-driven murine PGRN expression in a PGRN KO line (PGRN-KO NestinGrn ) to rescue PGRN in neurons. PGRN expression analysis in primary CNS cell cultures from naïve mice and in (non-) injured brain tissue from PGRN-KO NestinGrn revealed expression of PGRN in neurons but not in microglia. After experimental TBI, examination of the structural brain damage at 5 days post-injury (dpi) showed that the TBI-induced loss of brain tissue and hippocampal neurons was exacerbated in PGRN-KO Grnflfl mice (PGRN knockout with the mGrn fl-STOP-fl allele, Cre-negative), as expected, whereas the tissue damage in PGRN-KO NestinGrn mice was similar to that in PGRN-WT mice. Analysis of CD68 + immunofluorescent microglia and Cd68 mRNA expression showed that excessive microglial activation was rescued in PGRN-KO NestinGrn mice, and the correlation of brain injury with Cd68 expression suggested that Cd68 was a surrogate marker for excessive brain injury caused by PGRN deficiency. The results show that restoring neuronal PGRN expression was sufficient to rescue the exacerbated neuropathology of TBI caused by PGRN deficiency, even in the absence of microglial PGRN. Hence, endogenous microglial PGRN expression was not essential for the neuroprotective or anti-inflammatory effects of PGRN after TBI in this study. Graphical Abstract

Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin ( GRN ) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased expression of lysosomal transcripts, which may be driven by TFEB and related transcription factors. While this may be a compensatory response to lysosomal impairment, overproduction of lysosomal proteins may also contribute to FTD pathogenesis. To investigate how TFEB may contribute to disease in people with GRN mutations, we analyzed the effects of TFEB overexpression in progranulin-insufficient cells and mice. We generated GRN knockout HEK-293 cells ( GRN KO cells), which exhibited increased nuclear localization of TFEB and expression of lysosomal transcripts, but impaired autophagy. TFEB overexpression in GRN KO cells further increased lysosomal transcripts and partially normalized autophagy. We next injected an AAV vector expressing mouse Tfeb (AAV-TFEB) into the thalamus of Grn –/– mice, which accumulates lysosomal storage material. AAV-TFEB increased lysosomal transcripts and reduced immunoreactivity for SCMAS, a marker of lysosomal storage material, in Grn –/– thalamus. These data show that TFEB activity alleviates some autophagy-lysosomal deficits caused by progranulin insufficiency, suggesting potential utility of lysosome-based therapies for GRN -associated diseases.

Background Pathogenic heterozygous mutations in the progranulin gene ( GRN ) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers ( p  = 0.007) with a trend in non-carriers ( p  = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8 + T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC. Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.

Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor produced mainly by neurons and microglia in the central nervous system. Progranulin haploinsufficiency causes frontotemporal dementia (FTD). It is unclear to what extent neuronal versus microglial PGRN deficiency contributes to FTD pathology. In this study, we restored progranulin in neurons in progranulin knockout mice using Nestin-driven expression of mouse Grn transgene in a k nock o ut b ack g round (NesGrn KOBG). They were compared with full PGRN KO mice and floxed control mice that carry a loxP flanked STOP codon in front of m Grn transgene (Grn-flfl). The expected neuron-only PGRN rescue was confirmed at RNA and protein level in brain tissue and primary cells, and single nucleus RNA sequencing. Despite neuronal PGRN-restoration, there was no difference in microgliosis, astrogliosis, and microglia phenotypes as assessed by histology, microglia morphometry and bulk RNAseq showing strong upregulation of microglia-associated genes equally in both KO lines. However, a microglial subpopulation with a phagocyte signature expressing Gpnmb , Lgals3 , Atp6v0d2 and Apobec1 occurred only in PGRN KO brain, and accordingly, the loss of synapses and dendritic spines, which is caused by excessive synaptic pruning in PGRN KO mice, was partially attenuated in NesGrn KOBG mice. Lipidomic studies showed that phosphatidylserine eat-me-signals were increased in PGRN KO but not in NesGrn KOBG brain. Furthermore, some neuronal genes involved in axonal structure and dynamics were co-restored with progranulin in NesGrn KOBG mice. However, the modest improvement of neuronal health was not associated with an improvement of FTD-like behavior including hyperactivity, compulsive licking and impaired avoidance learning and memory. The results suggest that (still) viable neurons do not provide (sufficient) progranulin to prevent microgliosis but may shape the phenotype by presenting or hiding eat-me signals. Nonetheless, neuron-only-progranulin restoration may be insufficient to halt the progression of FTD.