Elevated levels of extracellular vesicles in progranulin‐deficient mice and FTD‐ GRN Patients

Sun

et al. 2022

Front. Aging Neurosci.

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.

Section: Discussionmentioning

confidence: 99%

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

Sun

et al. 2022

Front. Aging Neurosci.

“…Interestingly, ER stress can increase in response to progranulin administration [ 67 ] and impair insulin sensitivity in rodent models [ 67 , 68 ]. Within the pancreas of MEN1 transgenic mice, progranulin was found to be a potent stimulator of β-cell proliferation in pancreatic tumours [ 69 ] and in Grn −/− mice, progranulin is vital for endolysosomal trafficking regulation [ 70 ]. Interestingly, while β-cells are high secretory cells like neurons, the role progranulins play in insulin secretion or β-cell survival is unknown.…”

Section: Discussionmentioning

confidence: 99%

Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model

et al. 2021

Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.

“…Progranulin (PGRN) is a multifunctional growth factor expressed in a variety of tissues and involved in many physiological and pathological processes [21]. It is widely expressed in various cells of the body.…”

Section: Discussionmentioning

confidence: 99%

CSF PGRN May be Associated With Postoperative Delirium After Knee Replacement in Elderly Patients: The PNDABLE Study

Sun

et al. 2021

Preprint

BackgroundPostoperative delirium (POD) represents a serious complication following anesthesia and surgical procedures for patients undergoing surgical intervention (1). Little is known about the mechanisms underlying similarities in the core features between postoperative delirium (POD) and progranulin (PGRN)-related cognitive disorders. We herein investigated the relationship between preoperative CSF PGRN concentration and POD occurrence in the Han Chinese patients undergoing unilateral total knee arthroplasty.MethodsWe conducted an observational, prospective, and 1:1 matched (on age older than 65, the unilateral total knee arthroplasty, American Society of Anesthesiologist’ (ASA) physical status, duration of surgery, and intraoperative bleeding) case-control study. POD cases and non-POD controls were selected from the overall cohort using Confusion Assessment Method (CAM). Delirium severity was measured by the Memorial Delirium Assessment Scale (MDAS). CSF PGRN and core biomarkers were measured by ELISA using the microplate reader. The associations of CSF PGRN levels with POD risk and CSF core biomarkers were assessed.ResultsPOD incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN concentration between POD patients and controls (P<0.001), and CSF PGRN levels increased with age, as demonstrated by a significantly positive correlation (r=0.796, P<0.001).CSF PGRN levels to increase with CAM scores and MDAS scores, as demonstrated by significantly positive correlations (r=0.693, P<0.001; r=0.590, P<0.001). There were positive associations of CSF PGRN with T-tau (β = -0.501, P < 0.001) and P-tau (β = -0.470, P < 0.001) and negative associations of CSF PGRN with Aβ1–42 (β = -0.576, P < 0.001), Aβ1–40 (β = -0.488, P < 0.001), Aβ42/p-tau (β = -0.422, P < 0.001), and Aβ42 / T- tau (β = -0.395, P < 0.001) in POD patients. The ROC curve analysis of PGRN showed that PGRN concentrations had high diagnostic value for POD.ConclusionsCSF PGRN may be associated with the POD. Aβ pathology is associated with a decrease in CSF PGRN in the absence of tau deposition and neurodegeneration, whereas tau pathology and neurodegeneration is associated with an increase in CSF PGRN.Clinical Trial Registrationwww.clinicaltrials.gov, identifier ChiCTR2000033439.