sLRP1 Levels Research Articles

Peripheral transport proteins were associated with 4‐year cognitive decline in APOE ε4 non‐carriers: A longitudinal, population‐based study

AbstractBackgroundSoluble low‐density lipoprotein receptor‐related protein‐1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid‐β (Aβ).We aim to determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE) on their association.MethodCognitively normal subjects were followed‐up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini‐Mental State Examination (MMSE), and cognitive decline was defined as a ≥2‐point decrease of MMSE after 4‐years. The association between baseline sLRP1/sRAGE and 4‐year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship.Result769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4‐year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13‐3.86, p = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ε4 non‐carriers (adjusted OR = 1.60, 95% CI: 1.04‐2.48, p = 0.034).ConclusionIndividuals with lower levels of sRAGE had an increased risk of 4‐year cognitive decline in APOE ε4 non‐carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated.

A blood-based composite panel that screens Alzheimer’s disease

BackgroundBlood tests would be much easier to implement in the clinical diagnosis of Alzheimer’s disease (AD) as minimally invasive measurements. Multiple inspection technologies promoted AD-associated blood biomarkers’ exploration. However, there was a lack of further screening and validation for these explored blood-based biomarkers. We selected four potential biomarkers to explore their plasma levels in AD and amnestic mild cognitive impairment (aMCI) and developed a composite panel for AD and aMCI screening.MethodThe plasma concentrations of soluble low-density lipoprotein receptor-associated protein 1 (sLRP1), Gelsolin (GSN), Kallikrein 4 (KLK4) and Caspase 3 were measured in the discovery and validation cohort. The receiver operating characteristic (ROC) curve was generated to assess the classification panel with the area under the curve (AUC).ResultsA total of 233 participants (26 CN, 27 aMCI, and 26 AD in the discovery cohort, and 51 CN, 50 aMCI, and 53 AD in the validation cohort) with complete data were included in the study. The plasma concentrations of sLRP1 and Caspase 3 were significantly decreased in AD and aMCI when compared with those in the CN group. Compared with the CN group, the concentrations of KLK4 and GSN were increased in AD, but not in MCI. Interestingly, one of four proteins, sLRP1 in plasma level was higher in Apolipoprotein E (APOE) ε4 non-carriers than that in APOE ε4 carriers, especially among CN and MCI. No significant difference was found between females and males in the plasma levels of four proteins. The composite panel is based on four blood biomarkers accurately classifying AD from CN (AUC = 0.903–0.928), and MCI from CN (AUC = 0.846–0.865). Moreover, dynamic changes in the plasma levels of four proteins exhibited a significant correlation with cognitive assessment.ConclusionsAltogether, these findings indicate that the plasma levels of sLRP1, KLK4, GSN and Caspase 3 changed with the progression of AD. And their combination could be used to develop a panel for classifying AD and aMCI with high accuracy, which would provide an alternative approach for developing a blood-based test for AD and aMCI screening.

Association of Low Levels of Soluble Low-Density Lipoprotein Receptor-Related Protein-1 and COVID-19 Outcomes During the First Wave of Pandemic.

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytosis receptor that clears inflammatory proteins from circulation. LRP1 has anti-inflammatory effects that bindpro-inflammatory cytokines or ligands. LRP1 has a soluble form (sLRP1) which can be measured in serum. We report sLRP1 levels in hospitalized patients with COVID-19. The first objectiveof this study is to compare the sLRP1 levels between COVID-19 patientsand healthy controls. The second objective is to examine the association between sLRP1and the clinical outcome of COVID-19. All patients (20-80 years of age) were evaluated in a hospital using a positive PCR test for SARS‑CoV‑2 between April 1, 2020, and June 1, 2020. Controls (n=59) were selected from healthy subjects. sLRP1 levels were measured in patients from the emergency department (ED), inpatient service (IS), and the intensive care unit (ICU). The study included 180 cases. COVID-19 patients showed significantly lower sLRP1 levels compared to controls (1.43 (1.86) versus 2.27 (1.68) μg/mL, respectively, p<0.001). sLRP1 levels were 1.26 (1.81), 1.37 (1.65), and 1.74 (1.98) μg/mL in patients from ED, IS, and ICU, respectively (p=0.022). Patients who were admitted from ED displayed lower sLRP1 levels compared to those who were discharged (median sLRP1 levels were 0.86 versus 1.7 μg/mL, p=0.045). COVID-19 patients display significantly lower sLRP1 levels compared to the healthy controls. sLRP1 levels do not show any association with the clinical outcome of COVID-19. This study demonstrates that LRP1 displays a bidirectional course in COVID-19. A low sLRP1 level is a potential risk factor for susceptibility and hospital admission due to COVID-19. Further studies with larger sample sizes and longer follow-ups are needed to understand the long-term effects of novel biomarkers such as sLRP1 on the outcome of COVID-19.

Soluble low-density lipoprotein receptor-related protein 1 as a surrogate marker of carotid plaque inflammation assessed by 18F-FDG PET in patients with a recent ischemic stroke

Background18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) identifies carotid plaque inflammation and predicts stroke recurrence.AimOur aim was to evaluate the performance of soluble low-density lipoprotein receptor-related protein 1 (sLRP1) as an indicator of carotid plaque inflammation.MethodsA prospective study was conducted among adult patients with recent (< 7 days) anterior circulation ischemic stroke and at least one atherosclerotic plaque in the ipsilateral internal carotid artery. Patients underwent an early (< 15 days from inclusion) 18F-FDG PET, and the maximum standardized uptake value (SUVmax) within the plaque was measured. sLRP1 levels were measured in plasma samples by ELISA. The association of sLRP1 with SUVmax was assessed using bivariate and multivariable linear regression analyses. Hazard ratios (HR) were estimated with Cox regression to evaluate the association between circulating sLRP1 and stroke recurrence.ResultsThe study was conducted with 64 participants, of which 57.8% had ≥ 50% carotid stenosis. The multivariable linear and logistic regression analyses showed that sLRP1 was independently associated with (i) SUVmax within the plaque (β = 0.159, 95% CI 0.062–0.257, p = 0.002) and (ii) a probability of presenting SUVmax ≥ 2.85 g/mL (OR = 1.31, 95% CI 1.00–1.01, p = 0.046), respectively. Participants with stroke recurrence showed higher sLRP1 levels at baseline [6447 ng/mL (4897–11163) vs. 3713 ng/mL (2793–4730); p = 0.018].ConclusionssLRP1 was independently associated with carotid plaque inflammation as measured by 18F-FDG PET in patients with recent ischemic stroke and carotid atherosclerosis.

Resting heart rate is associated with novel plasma atherosclerosis biomarkers.

Resting heart rate (RHR) is a strong predictor of adverse cardiovascular outcomes. Both soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor for advanced glycation end products (sRAGE) are novel plasma biomarkers for atherosclerosis. In this study, we examined the potential associations between RHR and plasma sLRP1 and sRAGE levels and whether any associations might be modified by apolipoprotein E (APOE) ε4 carrier status. This cross-sectional study included 941 apparently healthy adults aged 40 years or older. Plasma sLRP1 and sRAGE levels were measured by a commercial enzyme-linked immunosorbent assay. APOE gene polymorphisms were analyzed by a polymerase chain reaction and Sanger sequencing. RHR was a significant determinant of log-transformed sLRP1 (β = 0.004; 95% confidence interval [CI], 0.002-0.007; P = 0.001) and log-transformed sRAGE (β = 0.005; 95% CI, 0.002-0.007; P <0.001) independently of age, sex, body mass index, blood pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, APOE ε4 carrier status was inversely associated with log-transformed plasma sLRP1 level (β = -0.072; 95% CI, -0.130 to -0.015; P = 0.01) and did not modify the relationship between RHR and plasma sLRP1 level. An elevated RHR was associated with increased sLRP1 and sRAGE values, which was not modified by APOE genotype. The underlying mechanism of this effect may be relevant to the progression of atherosclerosis.

Soluble LRP-1 in Parkinson’s disease: clues for paradoxical effects

Background: Low density lipoprotein receptor-related protein-1 (LRP-1) is highly expressed in the central nervous system and plays a role in neurodegenerative disorders. The available data on this subject-matter seem to support the presence of a correlation between LRP-1 levels and abnormal aggregation of a plurality of proteins, including tau, amyloid, and α‑synuclein. Understanding the molecular mechanisms underlying Parkinson’s disease (PD) is critical for development of new therapies. Aim: To investigate serum soluble LRP-1 (sLRP-1) concentrations in patients with PD and explored their potential role as a biomarker in diagnosis and prognosis of disease. Methods: Based on well-defined inclusion and exclusion criteria, we have included 133 PD patients and 45 healthy controls. The clinical severity was assessed using Hoehn Yahr and Unified PD Rating Scale (UPDRS). Following a fasting period, venous blood samples were taken, and centrifuged. Serum samples were stored until analysis. sLRP-1 was measured by ELISA assay. Results: The median of serum sLRP-1 levels was higher in PD patients compared to that in healthy controls, but without reaching a statistical significance. There was a positive, but statistically insignificant, correlation between sLRP-1 levels and duration of disease. sLRP-1 levels had a significant correlation with UPDRS Parts I and IV. Patients with hypertension showed lower levels of sLRP-1. Conclusion: The present study suggests that serum sLRP-1 concentrations are associated with the factors influencing prognosis of PD and disease severity. Further studies are needed to definitively determine whether or not sLRP-1 can be utilized as a diagnostic and prognostic biomarker for PD.

Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: A pilot study

BackgroundAlzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD.Materials and methodsPlasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD.ResultsAmong these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586–0.865); p = 0.0064] in diagnosis.ConclusionThe plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.

Soluble low density lipoprotein receptor-related protein-1 levels in the differential diagnosis of myopericarditis versus acute coronary syndrome

IntroductionDifferential diagnosis of myopericarditis (MPC) versus acute coronary syndromes (ACS) can be difficult in the emergency room (ER). Low density lipoprotein receptor-related protein-1 (LRP-1) is a transmembrane receptor with diverse biological functions. LRP-1 is increased after viral infections as a defense mechanism. sLRP-1 (soluble form) can be measured in the serum. We study the diagnostic sLRP-1 levels in patients with MPC, ACS and healthy controls. MethodsThe study included consecutive patients who were admitted between the dates of 1.1.2018 and 1.1.2019 with the diagnosis of MPC or ACS. All patients reported to the ER with chest pain (CP) and elevated cardiac troponin levels. Control group (n = 61) was selected from healthy subjects. In addition to routine laboratory work up, serum sLRP-1 concentrations were measured on admission. ResultssLRP-1 levels were significantly higher in MPC, compared to controls (p = 0.005) and ACS (p = 0.001). Median (IQR) sLRP-1 levels in MPC, controls and ACS were 7.39 (22.42), 2.27 (1.74), 2.41 (0.98) μg/ml, respectively (p = 0.004). Among the covariates: sLRP-1, age, gender, HDL-C and LDL-C; only sLRP-1 differentiated a diagnosis of MPC versus ACS (OR = 1684, p = 0,046, CI for OR (1008-2812). The area under the curve (AUC) was measured as 0.79 [CI 0.62–0.95] in ROC analysis, p = 0.001; sLRP-1 had 69% sensitivity and 85% specificity for diagnosis of MPC with a cut-off value of 4.3 μg/ml. ConclusionsLRP-1 is a potential biomarker in the differential diagnosis of MPC versus ACS in ER. Future studies are needed to evaluate and develop the utility of sLRP-1 as a diagnostic and prognostic biomarker in MPC.

Peripheral Transport Proteins Were Associated with 4-Year Cognitive Decline in APOE ɛ4 Non-Carriers: A Longitudinal, Population-Based Study.

Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid-β (Aβ). To determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE) on their association. Cognitively normal subjects were followed-up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini-Mental State Examination (MMSE), and cognitive decline was defined as a ≥2-point decrease of MMSE after 4 years. The association between baseline sLRP1/sRAGE and 4-year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship. 769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4-year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13-3.86, p = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ɛ4 non-carriers (adjusted OR = 1.60, 95% CI: 1.04-2.48, p = 0.034). Individuals with lower levels of sRAGE had an increased risk of 4-year cognitive decline in APOE ɛ4 non-carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated.

Low levels of soluble low-density lipoprotein receptor-related protein 1 in patients with type 2 diabetes mellitus and diabetic retinopathy

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a large transmembrane receptor. LRP-1 plays a role in diverse cellular processes, including lipid metabolism, cell growth, migration, and regeneration. Soluble form of LRP-1 (sLRP-1) can be detected in serum. sLRP-1 can serve as a biomarker of atherosclerosis and cardiometabolic diseases. This study investigated the concentrations of the circulating serum sLRP-1 in patients with retinopathy and type 2 diabetes mellitus.Fifty-two patients with diabetic retinopathy and 71 controls were enrolled based on well-defined eligibility criteria. Venous blood samples were collected after 12 h of fasting. sLRP-1 concentrations were measured using the commercially available ELISA in an accredited laboratory.The mean age of patients and control groups were 63.6 and 48.5 years, respectively. The median disease duration was 8.1 years. The median serum sLRP-1 levels were lower in patients with diabetic retinopathy compared to the controls (2.11 μg/mL versus 2.44 μg/mL, p = 0.034). No significant correlation was observed between the sLRP-1 and serum lipid levels.The sLRP-1 levels are low in patients with diabetic retinopathy compared to healthy controls, and future studies are needed to assess sLRP-1 as a potential biomarker in diabetic retinopathy.

Role of the LRP1-pPyk2-MMP9 pathway in hyperoxia-induced lung injury in neonatal rats.

To study the role of the low-density lipoprotein receptor-related protein 1 (LRP1)-proline-rich tyrosine kinase 2 phosphorylation (pPyk2)-matrix metalloproteinases 9 (MMP9) pathway in hyperoxia-induced lung injury in neonatal rats. A total of 16 neonatal rats were randomly placed in chambers containing room air (air group) or 95% medical oxygen (hyperoxia group) immediately after birth, with 8 rats in each group. All of the rats were sacrificed on day 8 of life. Hematoxylin and eosin staining was used to observe the pathological changes of lung tissue. ELISA was used to measure the levels of soluble LRP1 (sLRP1) and MMP9 in serum and bronchoalveolar lavage fluid (BALF). Western blot was used to measure the protein expression levels of LRP1, MMP9, Pyk2, and pPyk2 in lung tissue. RT-PCR was used to measure the mRNA expression levels of LRP1 and MMP9 in lung tissue. The hyperoxia group had significantly higher levels of sLRP1 and MMP9 in serum and BALF than the air group (P<0.05). Compared with the air group, the hyperoxia group had significant increases in the protein expression levels of LRP1, MMP9, and pPyk2 in lung tissue (P<0.05). The hyperoxia group had significantly higher relative mRNA expression levels of LRP1 and MMP9 in lung tissue than the air group (P<0.05). The activation of the LRP1-pPyk2-MMP9 pathway is enhanced in hyperoxia-induced lung injury in neonatal rats, which may be involved in the pathogenesis of bronchopulmonary dysplasia.

Abstract 12110: Low Density Lipoprotein Receptor-Related Protein 1 Levels and Syntax Score in Patients Presenting With ST Elevation Myocardial Infarction

Introduction: Low density lipoprotein receptor-related protein 1 (LRP1) protects against cardiomyocyte death through its ability to promote Akt- and ERK1/2-dependent survival pathways. LRP1 signaling is crucial in promoting cell survival. LRP1 inhibits cell death, and promotes the resolution of the inflammation and scar formation following tissue injury. LRP1 serves as a common receptor that mediates the myocardial cell protective effects of several signaling cascades. The association between LRP1 and severity coronary artery disease (CAD) in the setting of acute injury, such as ST elevation myocardial infarction (STEMI) remains to be elucidated. We measured the soluble LRP1 (sLRP1) levels in patients who presented with STEMI. CAD severity as assessed by SYNTAX score. Methods: We measured sLRP1 levels in 46 patients who presented with STEMI (mean age 61±13.3, M/F=36/10). The SYNTAX score was categorized as low (≤20), and high (&gt;20). The control group (n=60) was selected from outpatients without significant comorbidities (N=60, age 47±14.2, M/F=16/44). Results: Patients with STEMI and high SYNTAX scores display significantly lower sLRP1 levels compared to the group with STEMI and low syntax score and controls (p=0.035 and 0.016, respectively). Median (IQR) sLRP1 levels are 1.90 (0.67), 2.25 (2.56) and 2.26 (1.59) μg/ml, respectively (Figure 1). Conclusions: Previous studies indicate that LRP1 is cardioprotective by the activation of the reperfusion injury salvage kinase pathway after ischemia reperfusion. In this study we observe that sLRP1 decreases with the complexity of CAD in patients with STEMI. Low sLRP1 levels can be a biomarker of complex CAD. Various studies have reported the role of LRP1 in cardiac remodeling after myocardial injury. Future studies are required to estimate the utility of sLRP1 as a diagnostic and prognostic biomarker in STEMI. This work was supported by the Research Fund of Istanbul Medeniyet University (project number 1358).

Abstract 9960: Soluble Low Density Lipoprotein Receptor-related Protein-1 Levels As A Potential Biomarker In Covid19

Introduction: Low density lipoprotein receptor-related protein 1 (LRP1), is a multifunctional receptor. Soluble form (sLRP1) is measurable as a novel biomarker of inflammation and atherosclerosis. We hypothesize that sLRP1 levels can be associated with Covid19 disease onset and severity. Methods: We measured sLRP1 levels in 180 PCR positive, Covid19 patients admitted to the hospital (mean age 60± 19, M/F = 51/49). Controls (n=61) were selected from outpatients without significant comobidities. Results: Covid19 patients display significantly lower sLRP1 levels compared to the controls (p&lt;0.001). Covid19 patients are stratified based on the severity of Covid19 such as emergency room (n=44), inpatient service (n=95) and intensive care (n=41). Median sLRP1 levels are 2.27, 1.26, 1.36, and 1.73 μg/ml for controls, emergency room, inpatient service and intensive care patients, respectively. sLRP1 levels rise as severity of Covid19 increases (p= 0.022) (Figure 1). Other biomarkers of inflammation such as CRP display similar trends (Figure 2). Median hsCRP levels are 8.2, 10.2 and 16.4 mg/L for emergency room, service and intensive care patients respectively (p&lt;0.001). Conclusions: Previous studies indicate that LRP1 can be a defense mechanism in acute viral infections. Eliminating LRP1 by siRNA knockdown increases intracellular cholesterol and the infectious virus yield. LRP1 displays a bidirectional course in Covid19. Low sLRP1 can be a risk factor for Covid19. On the other hand, sLRP1 levels increase with disease severity as a defense response to infection. This work was supported by the Research Fund of Istanbul Medeniyet University (project number 1358).

Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-β Transport: A Population-Based Cross-Sectional Study.

Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ42 and sRAGE (β= 6.158, p = 0.049; β= 121.156, p < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ40, Aβ42, and sRAGE (β= -48.389, p = 0.017; β= -11.142, p = 0.020; β= -147.937, p = 0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ40: β= 0.034, p = 0.005; Aβ42: β= 0.010, p = 0.001) and HDL-c groups (Aβ40: β= 0.023, p = 0.033; Aβ42: β= 0.008, p = 0.002) but not in the high TG and low HDL-c groups. Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance.

LRP1 Expression in Sickle Cell Disorders: Insights into the Heterogeneity of Monocytic Response to Heme

Introduction: The importance of heme and its main scavenger hemopexin in the pathophysiology of sickle cell disease (SCD) has been demonstrated in animal models of SCD vaso-occlusion. Increase in monocyte-derived inflammatory cytokines in SCD can be attributed to heme-mediated activation of TLR4 signalling to produce TNF-alpha, and amplification of IL-6 production through a mechanism dependent on heme iron. This suggests that monocytes not only respond to heme but also have receptors to acquire it. We hypothesized that varying levels of heme and hemopexin in SCD could affect how circulating monocytes express LDL receptor related protein (LRP1), the receptor that targets the heme/hemopexin complex to degradation, which can be cleaved to produce a soluble form (s-LRP1).Methods: Peripheral venous blood samples from 119 subjects (39 healthy volunteers - AA, 44 homozygous sickle cell anemia patients - SS, 8 not on hydroxyurea treatment, and 36 hemoglobin SC disease patients - SC) were collected upon signed informed consent approved by the local ethics board. Automated complete blood counts and serum lactate dehydrogenase (LDH), bilirubin levels, and heme and hemopexin concentrations were determined. LRP1 expression was measured by mean fluorescence intensity through conventional flow cytometry (FACS Calibur and FACS DIVA software) in different monocyte subsets, classified according to their surface markers into classical (CD14++ CD16-), intermediate (CD14+ CD16+) and nonclassical (CD14dim CD16+) monocytes.Results and Discussion: As expected, reticulocyte count, LDH, bilirubin, and heme were significantly more elevated in SS than in SC patients when compared to AA subjects, and hemopexin was reduced in both patient groups (P <0.0001). Monocyte subsets differed significantly among the groups: SS and SC patients had more circulating intermediate and nonclassical monocytes than AA subjects (P <0.0001 and P=0.0002, respectively), which is compatible with the systemic inflammation that characterizes SCD. Noticeably, expression of membrane-bound LRP1 was significantly higher in monocytes from SS patients than in those from SC or AA. We also found that LRP1 expression was higher in intermediate and classical monocytes, which are characterized by higher CD14 expression, than in nonclassical CD14dim CD16+ cells. LRP1 expression correlated with hemopexin (rS=0.58, 95%CI 0.26-0.79, P=0.0012) and heme levels (rS=-0.39, 95%CI -0.58 to -0.16, P=0.0012) in SS, but not in SC patients. To address whether monocytic LRP1 expression was associated with circulating LRP1 levels, we measured s-LRP1 and found higher mean s-LRP1 levels in SS than in SC patients (5.52±2.32ug/ml vs. 4.23±2.08ug/mL, P=0.01), but AA subjects showed intermediate s-LRP1 levels (4.70±1.67ug/ml). In SS patients, s-LRP1 correlated with LDH (rS=0.45, 95% CI 0.22-0.64, P=0.0002), but not with all biomarkers of hemolysis, suggesting that s-LRP1 production may also be influenced by mechanisms other than hemolysis. Our data show that more severe hemolysis in SS patients (higher LDH, heme, and lower hemopexin levels) is associated with elevated expression of monocyte LRP1 and its circulating form s-LRP1. Our finding that LRP1 expression in intermediate monocytes correlates with heme and hemopexin levels, particularly in SS patients, suggests this cell type responds to excessive heme. Along with previous publications that this monocyte subtype upregulates heme oxygenase gene HMOX, this supports that monocytes equipped with LRP1 can capture heme/hemopexin complexes and detoxify heme. In addition, higher LRP1 expression in CD14+ circulating monocytes corroborates that these cells can respond simultaneously to free heme with TLR4/CD14-dependent TNF-alpha production and to hemopexin-bound heme captured by LRP1 to foster iron-mediated augmentation of IL-6 production (Dagur et al. 2017).Conclusions: This study highlights that some monocyte subtypes are more prone to capture heme/hemopexin complexes and may react to both free and hemopexin-bound heme, adding to the complexity of the pathophysiology of SCD. Modulation of monocyte differentiation towards subsets with lower responsiveness to heme may be further explored in SCD and other hemolytic diseases in the future.

The Role of Soluble Low-Density Lipoprotein Receptor-Related Protein-1 in Obstructive Sleep Apnoea.

Intermittent hypoxia in obstructive sleep apnoea (OSA) is related to inflammation and metabolic abnormalities. Soluble low-density lipoprotein receptor-related protein-1 (sLRP-1) is involved in anti-inflammatory and metabolic processes. However, its ligand, calreticulin (CALR) promotes pro-inflammatory responses and apoptosis. Our aim was to analyse the levels of these biomarkers in OSA. We recruited 46 patients with OSA and 30 control subjects. Inpatient sleep study was performed and fasting plasma samples were collected. Triglyceride glucose index (TyG) and atherogenic index of plasma (AIP) were calculated. Plasma sLRP-1 levels were significantly lower in the OSA group compared to the controls (1.67 (0.90–2.11) mg/L vs. 1.99 (1.53–3.51) mg/L; p = 0.04) after adjustment for age, gender, BMI and lipid profile. Plasma sLRP-1 concentrations were inversely related to age (r = −0.29), BMI (r = −0.35), cigarette pack years (r = −0.31), LDL-C (r = −0.34) and triglyceride levels (r = −0.27), TyG (r = −0.37) and AIP (r = −0.27) as well as to the oxygen desaturation index (ODI, r = −0.24; all p < 0.05). BMI (p = 0.01) and ODI (p = 0.04) were independent predictors for low sLRP-1 levels. CALR did not differ significantly between the two groups (0.23 (0.17–0.34) ng/mL vs. 0.24 (0.20–0.36) ng/mL p = 0.76). We detected lower sLRP-1 levels in subjects with OSA which could contribute to metabolic abnormalities associated with this disease.

Plasma amyloid‐β dynamics are regulated by the sleep‐wake cycle

AbstractBackgroundIt has been reported that sleep is an important physiological process and conducive to the elimination of brain metabolites and the recovery of brain function. Growing evidence suggested that sleep disorders were related to increased risk of AD and Aβ accumulation in the brain. Although peripheral Aβ clearance is associated with brain Aβ deposition, but the relationship between sleep‐wake cycle and plasma Aβ levels is unclear.MethodThirty cognitively normal healthy adults (aged 29.07 ± 8.12), sixteen males (53.33%), were recruited. Participants underwent normal sleep and peripheral blood samples were collected every three hours between 20:00 and 8:00 the next day. Plasma Aβ40, Aβ42, total tau, phosphorylated tau 181 (P‐tau), soluble low‐density lipoprotein receptor‐related protein (sLRP1) and soluble receptors for advanced glycation end products (sRAGE) levels were measured using ELISA kits.ResultPlasma Aβ40 concentration at 5:00 decreased significantly compared with plasma level at 23:00 (p=0.041), and there is a dynamic tendency of decreasing after sleep onset and increasing after awake, which is in accordance with the sleep‐wake cycle. Furthermore, Aβ40 and Aβ42 levels were positively correlated with plasma sLRP1 (Aβ40: r=0.1791, p=0.0283; Aβ42: r=0.1780, p=0.0293). However, there was no significant dynamic change in Aβ42, Tau, P‐tau, Tau, sLRP1 and sRAGE levels in twelve hours.ConclusionPlasma Aβ40 dynamics are regulated by the sleep‐wake cycle, and it may play a positive feedback regulating role in sLRP1 level.

Soluble Low-density Lipoprotein Receptor-related Protein 1 in Juvenile Idiopathic Arthritis.

This study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis (JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity. Plasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits. At enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; P = 0.02). Participants with 4 or fewer active joints, compared to those with 5 or more active joints, had significantly higher sLRP1 levels (mean ranks: 56.2 and 40.7, respectively; P = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = -0.235, P = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor-negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later. Plasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.

Relationship Between Peripheral Transport Proteins and Plasma Amyloid-β in Patients with Alzheimer's Disease Were Different from Cognitively Normal Controls: A Propensity Score Matching Analysis.

Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer's disease (AD). To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson's correlation analysis followed by multiple linear regression separately in the original population and matched participants. After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r = 0.222, p = 0.008) but not in patients with AD (r = 0.137, p = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β= 7.347, p = 0.014) but not in the AD group (β= 10.409, p = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

Association of Low-Density Lipoprotein Receptor-Related Protein 1 and Its rs1799986 Polymorphism With Mild Cognitive Impairment in Chinese Patients With Type 2 Diabetes

BackgroundLow-density lipoprotein receptor-related protein 1 (LRP1) is involved in cerebral glucose metabolism and amyloid-β clearance. This study aimed to investigate the pathogenetic roles of LRP1 and its rs1799986 polymorphism in mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM).MethodsA total of 166 Chinese patients with T2DM were enrolled and divided into two groups according to Montreal Cognitive Assessment (MoCA) scores. Neuropsychological tests were performed. Soluble LRP1 (sLRP1) levels were assessed using enzyme-linked immunosorbent assay, and the genotype of LRP1 rs1799986 was detected using the Sequenom method.ResultsDiabetic patients with MCI (n = 60) exhibited significantly lower plasma sLRP1 levels (p = 0.033) and worse glucose control (p = 0.009) than the healthy cognition controls (n = 106). Multivariate regression analysis revealed plasma sLRP1 levels [odds ratio (OR) = 0.971, p = 0.005] and HbA1c (OR = 1.298, p = 0.003) as a risk factor for MCI in diabetic patients, in addition to insulin use and hypertension. However, there was no association between plasma sLRP1 levels and HbA1c. After adjusting for age, sex, and education level, plasma sLRP1 levels in the MCI group were negatively correlated with Stroop Color Word Test B number (r = −0.335, p = 0.011), which represents selective attention, cognitive flexibility, and processing speed. Additionally, patients with T2DM carrying the T allele of LRP1 rs1799986 showed higher Auditory Verbal Learning Test (AVLT) delayed recall scores (p = 0.025).ConclusionDecreased plasma sLRP1 levels are associated with MCI, particularly with attention dysfunction, in patients with T2DM. Moreover, the T allele of LRP1 rs1799986 may decrease susceptibility to MCI. Further studies with large cohorts should be designed to elucidate the roles of LRP1 in hyperglycemia-induced cognitive decline.