Progranulin Levels Research Articles

Potential Value of Cerebrospinal Fluid Progranulin in the Identification of Postoperative Delirium in Geriatrics Patients Undergoing Knee Replacement: The Perioperative Neurocognitive Disorder and Biomarker LifestylE Study.

Objective: The aim of this study was to investigate whether progranulin (PGRN) levels in cerebrospinal fluid (CSF) were associated with postoperative delirium (POD) in geriatric patients undergoing knee replacement.Method: A total of 600 Han Chinese patients aged 65–90 years and who underwent unilateral total knee arthroplasty were included in the Perioperative Neurocognitive Disorder And Biomarker LifestylE (PNDABLE) study from June 2020 to November 2020. All participants were assessed using the Confusion Assessment Method and the Memorial Delirium Assessment Scale on postoperative days 1–7 (or before discharge) by an anesthesiologist. CSF PGRN and CSF biomarkers of POD were measured by ELISA. We analyzed the risk and protective factors of POD using the multivariate logistic regression, and the associations between CSF PGRN and CSF biomarkers of POD using multiple linear regression. We also explored whether the influence of CSF PGRN on POD was mediated by POD core pathology in linear regression models.Results: Postoperative delirium incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN between patients with POD and non-POD (NPOD). As for CSF biomarkers, CSF Aβ40, T-tau, and P-tau were risk factors for POD, while CSF PGRN, Aβ42, and Aβ42/Aβ40 were protective factors for POD, as shown by the multivariate logistic regression analysis. CSF PGRN was positively associated with CSF Aβ42 and was negatively associated with CSF Aβ40, T-tau, and P-tau in patients with POD. We found that the AUC was 0.795 (95% CI = 0.706, 0.867) for PGRN between POD and NPOD groups. We found the influence of CSF PGRN on POD was mediated by POD core pathology. The effect was considered partial mediation with the proportion of mediation varying from 44.92 to 62.07%.Conclusion: Cerebrospinal fluid PGRN may be a reasonably good prognostic factor for POD development. Overall, amyloid pathology and tau protein might partially mediate the influence of PGRN on POD.Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR2000033439.

Serum dipeptidyl peptidase-4 activity and progranulin level in polycystic ovary syndrome patients.

Background:Evidence showed that abnormal alteration of adipokines level may perform a key role in polycystic ovary syndrome (PCOS) pathogenesis. Dipeptidyl peptidase-4 (DPP4) and progranulin (PGRN) are two novel adipokines related to insulin resistance (IR). Thus, we aimed to determine the serum DPP4 activity and PGRN level in PCOS patients with and without IR, and non-PCOS women.Methods:Ninety women were recruited in the present study including 60 PCOS patients (divided into two groups of 30 IR and 30 non-IR) and 30 non-PCOS women. Serum levels of insulin, fasting blood glucose, PGRN, and DPP4 activity were measured, and IR indices were calculated.Results:DPP4 activity was significantly higher in PCOS-IR and PCOS-NIR patients than non-PCOS women (p<0.001, P=0.011, respectively), whereas no significant variation was detected between two groups of PCOS subjects. There was no significant difference in the level of PGRN in the three groups of the present study.Conclusion:The present study suggests that increasing DPP4 activity may be associated with PCOS.

Evaluation of serum progranulin levels in patients with psoriasis: A case-control study

Evaluation of serum progranulin levels in patients with psoriasis: A case-control study

A systematic review of progranulin concentrations in biofluids in over 7,000 people: Assessing the pathogenicity of GRN mutations and other influencing factors

AbstractBackgroundHeterozygous mutations in the GRN gene are a major cause of genetic frontotemporal dementia (FTD), accounting for an estimated 5‐10% of all people with FTD. GRN encodes for progranulin, with mutations causing haploinsufficiency, and being associated with significantly lower concentrations of progranulin in biofluids in mutation carriers compared to controls.MethodWe performed a search of the literature (up to December 2019) looking for publications reporting progranulin concentrations within serum, plasma or CSF in any medical condition including FTD and other forms of dementia. We then contacted all authors and asked if they were able to share anonymised data from their study including progranulin concentrations and clinical data including specific mutation if present, clinical diagnosis, age at onset of dementia, sex, and GRN rs5848 polymorphism. Data from 7,071 people was collated and analysed.ResultData on plasma progranulin concentrations measured using the Adipogen assay was available from 3,265 cases. Variability in levels across 109 different GRN mutations was seen and when split into mutation groups, missense variants outside the signal peptide had significantly higher levels compared to all other groups, suggesting that these variants are unlikely to be pathogenic. We established a plasma progranulin cut‐off value of 74.8ng/µL between pathogenic GRN mutation carriers and non‐carriers. We found that the GRN rs5848 polymorphism also affected plasma progranulin levels, with the TT genotype associated with significantly lower levels than CC. Sex differences were also seen, with significantly higher progranulin levels in females than males.ConclusionTogether these findings highlight the variable pathogenicity of different GRN mutations and the importance of considering other factors such as genetic risk factors and sex differences when looking at biofluid concentrations of progranulin. This is of particular relevance in upcoming clinical trials of progranulin‐associated FTD where progranulin levels are being measured as outcome measures.

AZP2006/EZEPROGIND neuroprotective effect in age-related cognitive decline and Alzheimer's disease progression.

AZP2006/EZEPROGIND is a disease-modifying small molecule that is currently in clinical development for the treatment of Progressive Supranuclear Palsy (PSP). Here we investigated its neuroprotective effect on in vitro and in vivo models of Alzheimer's disease (AD). We showed that AZP2006/EZEPROGIND neuroprotective action is mediated by Progranulin (PGRN) and correlated with a reduction of neuroinflammation. Primary rat cortical neurons cultured with microglia were injured with Aβ1-42 oligomers. We investigated the effect of AZP2006/EZEPROGIND on neuronal survival and neurite network (MAP2), synapses (PSD95/SYN), pTau (AT100), microglia activation (OX-41), neuroinflammation (IL-1β and IL-6) and PGRN levels. The PGRN mediated effect of AZP2006/EZEPROGIND was assessed by blocking Ab anti PGRN and siRNA for PGRN and/or Prosaposin (PSAP). AZP2006/EZEPROGIND (3 mg/kg/day) was also orally administered to the Senescence Accelerated Mouse-Prone 8 (SAMP8) mice, a spontaneous animal model of accelerated aging, from the age of 2, 4 or 6 months to 10 months. Learning and memory deficits were evaluated by Y-Maze Test and by Passive Avoidance Test. PGRN levels and of biochemical markers of oxidative stress (LPO), pTau (T181), Aβ1-42 , proinflammatory cytokines (IL-1β and IL-6), neuronal (NeuN) and microglial (Iba1) markers were studied by ELISA and IHC. In vitro, nM concentrations of AZP2006/EZEPROGIND significantly increased the neuron survival, the neurite network and the number of synapses. The incubation with blocking Ab anti PGRN and siRNA for PGRN and/or PSAP abolished these effects. Also, AZP2006/EZEPROGIND significantly decreased Tau hyperphosphorylation and reduced the neuroinflammation. The chronic treatment with AZP2006/EZEPROGIND significantly increased the Spontaneous Alternation in the Y-Maze Test and the Step-through Latency in the Passive Avoidance Test. We showed that AZP2006/EZEPROGIND was able to protect neurons, enhance synaptic function, decrease the hyperphosphorylation of Tau and reduce the neuroinflammation via PGRN. The chronic oral treatment was able to prevent, protect and restore the aged-related cognitive decline in the SAMP8 mice. We postulate that neuroprotective properties of AZP2006/EZEPROGIND not only could delay the progression of AD but also has the potential to reverse aged-related cognitive damages.

Six months interim analysis of the phase 2 study of AL001 in frontotemporal dementia patients carrying a granulin mutation

AbstractBackgroundFrontotemporal dementia (FTD) is a rare, early‐onset form of dementia and loss‐of‐function mutations in the progranulin gene (GRN) are a common cause of familial FTD. In the brain, progranulin (PGRN) is a key regulator of microglia activity and lysosomal function. AL001 is a human monoclonal IgG1 antibody that blocks and downregulates Sortilin, a receptor in the key degradation pathway of PGRN, and is being developed by Alector for the treatment of carriers of GRN mutations causative of FTD (FTD‐GRN). Restoring PGRN levels may be an effective therapeutic approach in FTD, and AL001 was shown to normalize CSF PGRN levels in GRN mutation carriers in a Phase 1 study.MethodINFRONT‐2 is an open‐label, Phase 2 study in GRN mutation carriers to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL001 administered intravenously every four weeks. Lumbar punctures and MRI scans were performed at baseline and every 6 months. Clinical assessments were done every 3 months. Fluid biomarkers in plasma and CSF were analyzed using multiple platforms.ResultPreliminary results demonstrated that AL001 was generally safe and well tolerated in FTD‐GRN participants in INFRONT‐2. Chronic dosing led to a sustained increase in PGRN levels to the normal range in FTD‐GRN carriers. Preliminary CSF biomarker data related to key aspects of FTD‐GRN pathophysiology, namely changes in levels of lysosomal proteins and markers of inflammation, will be presented for FTD‐GRN participants who received AL001 for 6 months. In addition, updated biomarker data related to neurodegeneration will be presented.ConclusionThere is a high unmet need for effective therapies in FTD. AL001 is being developed for the treatment of FTD‐GRN to reduce the rate of neurodegeneration by increasing levels of PGRN and disrupting the pathophysiologic cascade associated with FTD‐GRN. INFRONT‐3 is an ongoing, pivotal Phase 3 study to evaluate if AL001 can slow or stop disease progression in carriers of GRN mutations.

Progranulin and chemerin plasma level in obese patients with type 2 diabetes treated with a long-acting insulin analogue and premixed insulin analogue.

Diabetes, referred to as the first non-infectious epidemic, covers a heterogenous group of metabolic diseases marked by hyperglycemia resulting from a defect of insulin secretion and/or insulin resistance. Highly endocrine active adipocytes, particularly those located in white adipose tissue, constitute a source of cytokines, growth factors and complement component as well as adipocytokines including chemerin and progranulin could be the key molecules in the pathomechanism of hypertension, dyslipidemia, metabolic disorders or diabetes type 2. In this study, it was decided to verify the existence of possible relationships between the plasma concentration of progranulin and chemerin and the values of intermediate indices of insulin sensitivity and insulin resistance in patients, both before and after the 6-month insulin therapy by long-acting insulin analogue and premixed insulin analogue. The level of laboratory parameters in blood plasma collected from the control group and from obese individuals with type 2 diabetes mellitus was estimated with the test kits using enzyme-linked immunosorbent assay (ELISA): the test of Mediagnost E103 GmbH GmbH, Reutlingen, Germany for progranulin; the test of BioVendor R&D, Brno, Czech Republic for chemerin. The aim of this study was to assess the progranulin and chemerin plasma level in obese individuals with type 2 diabetes, before and after 6 months of pharmacological treatment with a long-acting analogue human insulin or premixed insulin. In the blood plasma of untreated diabetics - in contrary to progranulin plasma concentration in diabetic patients after management implementation - progranulin was found to occur in a significantly higher concentration in relation to the level of this protein in the blood plasma of control group individuals. Despite the fact that 6-month therapy, both with the insulin mixture and with the long-acting analogue in people with diabetes, does not significantly affect the plasma chemerin concentration, the high, negative correlation between the progranulin and chemerin levels in the blood of individuals of the control group, and a positive one between the levels of progranulin and chemerin in people with diabetes before and after treatment was found. The conducted studies indicated the modified, in the course of diabetes type 2, mutual quantitative relations between progranulin and chemerin - the biological mediators of systemic metabolism, reflecting their active participation in the pathogenetic changes underlying type 2 diabetes. The obtained study results indicate a modification of mutual relationships of the adipocytokines assessed in the paper - progranulin and chemerin, associated with the development of the systemic inflammatory response occurring in the course of obesity which, by inducing insulin resistance, may consequently lead to type 2 diabetes. Taking into consideration the fact that the plasma progranulin and chemerin concentrations in obese patients with type 2 diabetes subjected to pharmacotherapy have not been assessed so far, it is possible that the obtained study results may cast light on the potential influence of the applied treatment on the systemic changes of the both adipocytokines involved in the pathomechanism of the mentioned disorder and thus create the possibility of implementing new therapeutic strategies in the management of patients with diabetes, which is an increasingly common, fast-spreading metabolic disease considered as a non-infectious epidemic of the 21st century.

Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway.

Genetic variants in Granulin (GRN), which encodes the secreted glycoprotein progranulin (PGRN), are associated with several neurodegenerative diseases, including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer’s disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying factors that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration and could reveal novel potential therapeutic targets. Here, we report that modulation of the endocytosis/lysosomal pathway via reduction of Nemo-like kinase (Nlk) in microglia, but not in neurons, can alter total brain Pgrn levels in mice. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through the endocytosis/lysosomal pathway, specifically in microglia. Furthermore, genetic interaction studies in mice showed that Nlk heterozygosity in Grn haploinsufficient mice further reduces Pgrn levels and induces neuropathological phenotypes associated with PGRN deficiency. Our results reveal a mechanism for Pgrn level regulation in the brain through the active catabolism by microglia and provide insights into the pathophysiology of PGRN-associated diseases.

Progranulin correlated with rapid progressive interstitial lung disease in dermatomyositis with anti-melanoma differentiation-associated gene 5 antibody.

This study aimed to detect the expression of progranulin (PGRN) and elucidate associations with clinical features in dermatomyositis (DM) patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody. We enrolled 40 DM patients with anti-MDA5 antibody, 20 patients with antisynthetase syndrome (ASS; disease control), and 20 healthy individuals (healthy control, HC). The clinical features of patients with anti-MDA5 antibody and anti-histidyl-tRNA antibody were collected. The level of PGRN in the serum was tested by ELISA. The PGRN levels in DM patients with anti-MDA5 antibody (166.74 ± 97.95ng/ml) were significantly higher than those in patients with ASS (82.66 ± 40.50ng/ml; p < 0.001) and in HC (42.34 ± 18.69ng/ml; p < 0.001). Patients with rapid progressive interstitial lung disease (RP-ILD) in DM with anti-MDA5 antibody (213.57 ± 114.05ng/ml) had higher levels of PGRN than those without RP-ILD (135.51 ± 72.41ng/ml; p = 0.012). ROC analysis showed an AUC value at 0.715 (95% CI, 0.541-0.888) for diagnosis of RP-ILD in DM patients with anti-MDA5 antibody. The expression of PGRN was positively correlated with the levels of ALT, AST, CK, LDH and ferritin (all p < 0.05). Our results indicated PGRN had great potential as a valuable serum marker of RP-ILD in DM with anti-MDA5 antibody. Key Points The level of PGRN was elevated in DM patients with anti-MDA5 antibody, especially for those with RP-ILD.

Serum progranulin levels in axial spondyloarthropathy and relationship with clinical features.

Objectives In this study, we aimed to investigate the serum progranulin (PGRN) levels in patients with axial spondyloarthropathy (AxSpA) and to identify the correlation between disease activity, symptom severity, acute phase reactant (APR), and serum PGNR levels in patients with AxSpA.Patients and methods This prospective, cross-sectional study included a total of 152 patients (105 males, 47 females; mean age: 41.8±10.3; range 20 to 65 years) with AxSpA according to the 2009 Assessment of SpondyloArthritis Society (ASAS) criteria who received treatment and 100 healthy individuals (61 males, 39 females; mean age 43.4±14.2; range 20 to 65 years) between February 2018 and February 2019. Serum PGRN levels from the venous blood were analyzed in both groups. The clinical AxSpA assessment scales were used in the patient group. Erythrocyte sedimentation rate and C-reactive protein levels were examined.Results The mean serum PGRN level was 6.9±5.4 ng/mL in the patient group and 11.2±6.0 ng/mL in the control group. Serum PGRN level was significantly higher in the control group (p<0.001). No significant correlation was found between the PGRN levels and disease activity, symptom severity, duration of disease, and age of the patient (p>>0.05). Serum PGRN levels were significantly higher in female patients in the patient group (p<0.01). In the control group, the serum PGRN levels of individuals with a high body mass index were significantly higher (p=0.001).Conclusion Serum PGRN levels of patients with AxSpA who are under treatment and follow-up are significantly lower than healthy individuals. Serum PGRN levels in female patients with AxSpA are also significantly higher than male patients. Serum PGRN levels do not seem to be related to disease activity.

Serum progranulin as a predictive marker for high activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BackgroundThis study investigated whether serum progranulin could act as a predictive marker for high disease activity of antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV).MethodsFifty‐eight AAV patients were included in this study. Clinical and laboratory data were obtained at blood collection. The Short‐Form 36‐Item Health Survey Physical and Mental Component Summaries (SF‐36 PCS and SF‐36 MCS), Birmingham Vasculitis activity score (BVAS), Five‐Factor Score (FFS), and Vasculitis Damage Index (VDI) were assessed as AAV‐specific indices. Whole blood was collected and serum samples were isolated and stored at −80°C. Serum progranulin concentration was quantified by ELISA kits.ResultsThe median age of patients was 63.0 years (19 men). The median BVAS was 11.0, and the median serum progranulin level was 49.0 ng/ml. Serum progranulin was significantly correlated with BVAS, FFS, erythrocyte sedimentation rate, C‐reactive protein level, SF‐36 PCS, haemoglobin, and serum albumin. Severe AAV was arbitrarily defined as the highest tertile of BVAS (BVAS ≥16). When the cut‐offs of serum progranulin were set as 55.16 ng/ml and 43.01 ng/ml for severe AAV, AAV patients with serum progranulin ≥55.16 and 43.01 ng/ml had significantly higher risks of severe AAV than those without (relative risk (RR) 4.167 and 4.524, respectively).ConclusionsProgranulin might play an anti‐inflammatory role in AAV pathogenesis and serum progranulin could be used as a predictive marker for high activity of AAV.

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. ClinicalTrials.gov Identifier: NCT02149160.

Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Patients.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed C9orf72 hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of “classical” (Aβ42, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with C9orf72 repeat expansion and 11 patients with causative variants in other genes (three in TARDBP, three in GRN, three in VCP, one in FUS, one in SOD1). In ALS patients, we found that levels of phospho-tau were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare C9orf72 and APP variants had lower levels of total tau and Aβ42, respectively. Plasma progranulin levels were decreased in patients carrying GRN pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations.

Elevated Serum Levels of Progranulin and Soluble Vascular Cell Adhesion Molecule-1 in Patients with COVID-19.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the angiocentric inflammation and angiogenesis, yet the molecules involved in this process remain to be determined.MethodsWe did a cross-sectional study of a cohort of patients with COVID-19 in Zunyi, China between February 1 and March 30, 2020. Serum concentrations of PGRN were determined by enzyme-linked immunosorbent assay in patients with COVID-19 at hospital admission and at discharge. In parallel, the serum levels of soluble adhesion molecules, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin), and E-selectin (sE-selectin) were assayed by a human adhesion molecule multiplex kit. The association between serum PGRN levels and other laboratory test results was analyzed by Spearman correlation analysis.ResultsAt baseline, the median serum PGRN levels in patients with COVID-19 were 94.8 ng/mL [interquartile range (IQR): 66.6–119.6 ng/mL], which was significantly elevated compared with those in healthy controls (46.3 ng/mL, IQR: 41.8–55.6 ng/mL). Moreover, the median serum sVCAM-1 levels were significantly higher in COVID-19 patients (1396.0 ng/mL, IQR: 1019.1–1774.8 ng/mL) than those in healthy controls (612.4 ng/mL, IQR: 466.4–689.3 ng/mL). However, the levels of sICAM-1, sP-selectin, and sE-selectin were not significantly elevated in patients with COVID-19 when compared to healthy controls. Further analysis showed that serum PGRN levels were significantly positively associated with sVCAM-1 (r= 0.675, P= 0.008) and inversely with sICAM-1 (r= −0.609, P= 0.021) and aspartate aminotransferase levels (r= −0.560, P= 0.037) in patients with COVID-19 at hospital admission. In COVID-19 patients, serum PGRN and sVCAM-1 levels fell significantly after successful treatment.ConclusionThe present study demonstrates elevated serum PGRN and sVCAM-1 levels in patients with COVID-19, which may provide clues as to the mechanisms underlying the pathogenesis of COVID-19. Further studies are warranted to evaluate the potential of PGRN and sVCAM-1 as biomarkers and investigate their role in the pathogenesis of COVID-19.

AZP2006, a new promising treatment for Alzheimer\u2019s and related diseases

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia

We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks. RedPenMC had an increased ratio of GRN-expressing microglia, higher levels of activating histone mark H3k4me3 in microglia and lower levels of the repressive chromatin marks H3k9me1 and H3k9me3 in the frontal cortex than her affected mutation carrier son and evidence of higher protein levels of progranulin in both plasma and brain homogenates. Although the study is limited to one case, the results support that restoring brain progranulin levels may be sufficient to escape neurodegeneration and FTD. In addition to previously identified modifier genes, it is possible that epigenetic marks may contribute to the increased progranulin expression in cases of reduced penetrance. These findings may stimulate similar follow-up studies and new therapeutic approaches.

Progranulin and tumor necrosis factor-alpha in lean polycystic ovary syndrome patients

Objective In this study, levels of progranulin (PGRN) and tumor necrosis factor-alpha (TNF-α) were measured to detect the presence of inflammation in lean polycystic ovary (PCOS) patients. Methods 40 lean PCOS patients were assessed by Rotterdam criteria. Forty healthy women with regular menstrual cycles and without biochemical and clinical hyperandrogenism were involved in our study. Blood samples were taken from the patient and control groups for the measurement of progranulin (PGRN), tumor necrosis factor-alpha (TNF-α), lipid parameters, glucose, insulin, and other hormones. Results Serum PGRN and TNF-α levels were significantly higher in patients with lean PCOS, compared with the control group (p = .037, p = .041). PGRN levels were positively correlated with TNF-α levels in lean PCOS patients. Conclusion PGRN is known as a ligand for the TNF-α receptor. PGRN level increase in lean PCOS patients may be due to inhibiting the inflammatory effects of TNF-α. To observe the PGRN and TNF-α connection in obesity, further study is needed in obese PCOS patients and obese control groups.

Progranulin deficiency in Iba-1+ myeloid cells exacerbates choroidal neovascularization by perturbation of lysosomal function and abnormal inflammation

BackgroundAge-related macular degeneration (AMD) is the principal cause of permanent blindness among elderly individuals worldwide. Chronic inflammation in the subretinal space is associated with a progression of exudative AMD. Progranulin (PGRN) is a growth factor secreted from myeloid cells and plays an important role in controlling the lysosomal function. A deficiency in PGRN leads to inflammation of the neurons in the central nervous system. The purpose of this study was to investigate the role played by PGRN in the size of the choroidal neovascularization (CNV) in laser-induced CNV mice.MethodsCNVs were induced in C57BL/6J mice by laser photocoagulation of the retina. The expression of PGRN and the accumulation of Iba-1+ cells around the sites of the CNVs were determined. Grn−/−, Grn+/−, and Grn+/+ mice with laser-induced CNVs were also studied. To evaluate the effect of macrophages on the inflammation, we used a macrophage cell line (RAW264.7) in which the expression of PGRN was knocked down by RNA interference and peritoneal macrophages derived from Grn−/− and Grn+/+ mice. These cells were incubated under hypoxic conditions (1% O2).ResultsIba-1+ myeloid cells migrated and accumulated in the photocoagulation-induced CNV areas, and the CNV lesions secreted high levels of PGRN in Grn+/+ mice. The size of the CNVs was larger in Grn−/− mice than in Grn+/− and Grn+/+ mice. In Grn−/− mice, the number of ocular-infiltrating Iba-1+ cells around the CNV was higher, and these cells produced more VEGF-A than the cells in the Grn+/+ mice. PGRN-silencing of RAW264.7 cells led to abnormal activation of the cells. In addition, hypoxic conditions promoted the production of proangiogenic and proinflammatory cytokines from PGRN-deficient macrophages. Interestingly, the expression level of lysosome-associated proteins and the number of activated lysosomes increased in PGRN-deficient macrophages.ConclusionsThese findings indicate that PGRN deficiency in Iba-1+ cells activates the lysosomal function that then leads to abnormal inflammation. The aberrant activation of Iba-1+ myeloid cells might contribute to the progression of the CNV and the regulation of these cells might be a novel therapeutic target for exudative AMD.

SY3.3. Role of ultrasound in ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder defined through the involvement of upper and lower motor neuronal systems. The clinical and neurophysiological investigation remains the gold standard in the diagnosis of ALS due to the lack of a definitive biomarker. Recently, a high-resolution ultrasound technique has been developed and is becoming popular in the field of the diagnosis of neuromuscular diseases. Also in the diagnosis and monitoring of ALS, neuromuscular ultrasound provides complementary information to clinical assessment and neurophysiological testing as well as insights into the underlying pathophysiology of this disease. Muscle ultrasound is used for detecting widespread fasciculations and assessing muscle atrophy. Dynamic diaphragm thickness change can be measured by ultrasound and its change correlates with respiratory function. Bulbar muscle ultrasound is also useful for the assessment of bulbar dysfunction and dysphagia. Nerve ultrasound can detect a reduction in cross-sectional area (CSA) and diameter of peripheral nerves and nerve roots in patients with ALS, reflecting nerve atrophy due to motor nerve axonal loss. These findings help us to distinguish ALS from mimicking diseases such as multifocal motor neuropathy, in which increased nerve size is observed. In addition, nerve CSA has a correlation with CSF level of progranulin which increases to maintain structure and function of neurons. Ultrasound examination is an operator-dependent and machine-dependent. However, the neuromuscular ultrasound technique is easy to learn. To have a skill of neuromuscular ultrasound is valuable to diagnose ALS accurately and to understand the pathophysiology of ALS deeper.

Progranulin attenuated asthma inflammation by inhibiting the expression of IL-6

Objective: To investigate the role and mechanism of progranulin (PGRN) in asthma. Methods: Control group and model group were set up in wild and IL-6 knockout (IL-6 ko) mice, respectively. For asthma model, mice were intraperitoneally sensitized with 100 μg OVA on days 0 and 7, followed by aerosol challenges with 5% OVA for 30 min per day from day 14 to 21, and mice were sacrificed 24 h after the last challenge. The mice in control group were treated in the same way with PBS. Bronchoalveolar lavage fluid (BALF) was collected for leukocytes count and differential count. The pathological changes of lung tissues were observed by H&E staining. The cytokines in lung homogenate, serum and BALF were detected by Q-PCR and ELISA. The in vitro model of asthma was induced by stimulating A549 or BEAS-2B cells with IL-13. Each group was replicated in three wells and four groups were designed: PBS group, IL-13 treatment group, IL-13 + rhPGRN treatment group, inhibitors of p38 phosphorylation (SB203508) treatment group. The cells or supernatant were collected after 0~48 h. PGRN and IL-6 levels were determined by Q-PCR and ELISA, the level of p38 phosphorylation was tested by Western blot (WB). Results: Compared with control group, PGRN levels were decreased in lung homogenate and BALF (P＜0.05), and PGRN presented a downtrend in serum, however, the level of IL-6 in BALF was increased in asthma mice (P＜0.01). In IL-6 ko asthma mice, compared with the wild asthma mice, leukocytes, especially neutrophils in BALF were decreased (P＜0.05), but PGRN was increased (P＜0.05), lung pathological damage was significantly alleviated. In vitro experiments, compared with PBS group, PGRN level was decreased (P＜0.05), IL-6 level was increased (P＜0.01), phosphorylation of p38 was activated in IL-13 treatment group. Compared with IL-13 treatment group, in IL-13 + PGRN treatment group, IL-6 level was decreased (P＜0.05); phosphorylation of p38 was inhibited (P＜0.05); and the production of IL-6 (P＜0.05) was decreased after treatment with inhibitor of p38 phosphorylation. Conclusion: PGRN inhibited the production of IL-6 by suppressing the p38 phosphorylation to alleviate asthmatic airway inflammation.