C1q Levels Research Articles

Fatal Recurrent Angioedema with Systemic Section Lupus Erythematosus in a Young Female: A Disturbing Decline

Recurrent angioedema is a particularly puzzling problem for clinicians worldwide. The cause is often idiopathic with chronic angioedema recurring over weeks to months. Intake of certain drugs and contact with other offending agents can also induce chronic angioedema. In systemic lupus erythematosus patients, recurrent angioedema may be due to an acquired deficiency of C1 inhibitor (C1-INH) caused most probably due to formation of antibody against C1-INH molecule. A 26-year-old female, who had systemic lupus erythematosus, presented to the Emergency Department with the chief complaint of puffiness of face, swelling of lips and bilateral lower limbs since one day, which occurred following application of aloe vera cream thrice within a duration of 24 hours. Upon investigations, absolute eosinophil count was raised while C4 and C1q levels were reduced. A diagnosis of acquired angioedema was made. Patient was managed with corticosteroids, cyclophosphamide, antibiotics, antihistaminics, oxygen support and other supportive measures. However, the patient’s condition declined further and she succumbed on day 5 of admission. Therefore, this report highlights the importance of chronic angioedema in a patient with systemic lupus erythematosus and the potential lethal outcome that it can result into.

Complement regulation in ovine lymph nodes during early pregnancy.

A fetus changes immune responses in the uterus and the maternal immune system, and lymph nodes are associated with regulating maternal adaptive immunity. Complement activation is associated with abnormal pregnancy in mice and humans. The aim of the present study was to explore the expression levels of complement components in maternal lymph nodes during early pregnancy in sheep. Maternal inguinal lymph nodes were sampled on day 16 of the estrous cycle, and days 13, 16 and 25 of gestation in ewes. Reverse transcription-quantitative PCR, western blotting and immunohistochemical analyses were used to detect the expression levels of complement components C1q, C1r, C1s, C2, C3, C4a, C5b and C9 in the lymph nodes. The results revealed that the protein and mRNA levels of C1q, C1s and C5b were enhanced during early pregnancy, and that C1r and C4a were upregulated at day 25 of pregnancy. The mRNA and protein levels of C2 and C9 peaked at day 16 of pregnancy, but C3 was decreased at day 25 of pregnancy. C3 protein was located in the subcapsular sinuses and lymph sinuses of the maternal lymph node. In summary, the present study detected changes in the expression levels of complement components in maternal lymph nodes, which may be associated with maternal immune regulation during early pregnancy in sheep.

C1q inhibits differentiation of oligodendrocyte progenitor cells via Wnt/β-catenin signaling activation in a cuprizone-induced mouse model of multiple sclerosis

Multiple sclerosis (MS) is a chronic central nervous system demyelinating disease of autoimmune originate. Complement C1q, a complex glycoprotein, mediates a variety of immunoregulatory functions considered important in the prevention of autoimmunity. Although we found that the increased serum C1q level was highly associated with the Fazekas scores and T2 lesion volume of MS patients, the effect and mechanism of C1q on demyelination remains unclear. Cluster analysis and protein array results showed that serum Wnt receptors Frizzled-6 and LRP-6 levels in MS patients were both increased, we proposed that C1q may be involved in demyelination via Wnt signaling. The increased C1q protein levels in the serum and brain tissue were confirmed in a cuprizone (CPZ)-induced demyelination mice model. Moreover, CPZ treatment induced significant increase of LRP-6 and Frizzled-6 protein in mice corpus callosum. LRP-6 extra-cellular domain (LRP-6-ECD) level in the serum and cerebrospinal fluid (CSF) of CPZ mice also significantly increased. Knockdown of the subunit C1s of C1 not only substantially attenuated demyelination, promoted M2 microglia polarization and improved neurological function, but inhibited β-catenin expression and its nuclear translocation in oligodendrocyte progenitor cells (OPCs). In vitro, C1s silence reversed the increased level of LRP-6-ECD in the medium and β-catenin expression in OPCs induced by C1q treatment. Meanwhile, inhibition of C1s also markedly lowered the number of EDU positive OPCs, but enhanced the number of CNPase positive oligodendrocyte and the protein of MBP. The present study indicated that C1q was involved in demyelination in response to CPZ in mice by preventing OPC from differentiating into mature oligodendrocyte via Wnt/β-catenin signaling activation.

Serum Level of Complement C1q is Associated with Contrast-Associated Acute Kidney Injury in Patients Undergoing Emergency Percutaneous Coronary Intervention.

BackgroundAs an inflammatory factor, complement C1q is related to the prevalence and progression of atherosclerosis; however, in patients undergoing emergency percutaneous coronary intervention (PCI), it is unclear whether C1q is related to the prevalence of contrast-associated acute kidney injury (CA-AKI).MethodsFrom November 2018 to March 2021, 1182 patients who underwent emergency PCI were continuously recruited. Patients were divided into CA-AKI group (n = 234) and non-CA-AKI group (n = 948). CA-AKI was defined as an increase in serum creatinine from the baseline level (≥25% or ≥0.5 mg/dL) 48–72 hours after contrast exposure. All subjects were tested for serum C1q levels when they were admitted to the hospital.ResultsAmong the 1182 patients undergoing emergency PCI, 234 patients (19.80%) developed CA-AKI. The level of preoperative serum complement C1q in the CA-AKI group was significantly higher than that in the non-CA-AKI group. Logistic regression and restricted cubic spline analyses showed that the incidence of CA-AKI was positively associated with the serum C1q level pre-PCI. Univariate and multivariate logistic regression analyses showed that C1q was an independent predictor of whether CA-AKI occurred after emergency PCI. The area under the curve (AUC) of the C1q was 0.703 [95% confidence interval (CI) 0.667–0.739] in patients receiving emergency PCI. CA-AKI model included the following three predictors: C1q, eGFR, and IABP use. The AUC of forecast probability was 0.718 [95% CI 0.682–0.754].ConclusionIn patients receiving emergency PCI procedure, a high C1q level before PCI is associated with the increased risk of CA-AKI.

Journal Digest: Post-COVID Depression; Locus Coeruleus and Alzheimer’s; CY-BOCS Reliability; and More

Journal Digest: Post-COVID Depression; Locus Coeruleus and Alzheimer’s; CY-BOCS Reliability; and More

Activation of the Complement System in Patients with Cancer Cachexia.

Simple SummaryPatients with cancer often suffer from severe weight loss as a result of the wasting of skeletal muscle and fat tissue. This has a strong negative impact on the patient’s prognosis and quality of life. Inflammation is thought to contribute to weight loss in cancer. To enable the future targeting of inflammation in patients with cancer who experience weight loss, we set out to characterize an important pro-inflammatory component of the immune system: the complement system. The blood levels of several elements of the complement system were analyzed in patients with and without weight loss and inflammation. We found that complement factors were activated specifically in patients with both weight loss and inflammation. Since complement inhibitory drugs are already on the market, these findings may open new opportunities for treating inflammation-mediated weight loss in patients with cancer.Systemic inflammation is thought to underlie many of the metabolic manifestations of cachexia in cancer patients. The complement system is an important component of innate immunity that has been shown to contribute to metabolic inflammation. We hypothesized that systemic inflammation in patients with cancer cachexia was associated with complement activation. Systemic C3a levels were higher in cachectic patients with inflammation (n = 23, C-reactive protein (CRP) ≥ 10 mg/L) as compared to patients without inflammation (n = 26, CRP < 10 mg/L) or without cachexia (n = 13) (medians 102.4 (IQR 89.4–158.0) vs. 81.4 (IQR 47.9–124.0) vs. 61.6 (IQR 46.8–86.8) ng/mL, respectively, p = 0.0186). Accordingly, terminal complement complex (TCC) concentrations gradually increased in these patient groups (medians 2298 (IQR 2022–3058) vs. 1939 (IQR 1725–2311) vs. 1805 (IQR 1552–2569) mAU/mL, respectively, p = 0.0511). C3a and TCC concentrations were strongly correlated (rs = 0.468, p = 0.0005). Although concentrations of C1q and mannose-binding lectin did not differ between groups, C1q levels were correlated with both C3a and TCC concentrations (rs = 0.394, p = 0.0042 and rs = 0.300, p = 0.0188, respectively). In conclusion, systemic inflammation in patients with cancer cachexia is associated with the activation of key effector complement factors. The correlations between C1q and C3a/TCC suggest that the classical complement pathway could play a role in complement activation in patients with pancreatic cancer.

Inhibition of Complement C1s By Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Efficacy and Safety Results from the Randomized, Placebo-Controlled Phase 3 CADENZA Study

Inhibition of Complement C1s By Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Efficacy and Safety Results from the Randomized, Placebo-Controlled Phase 3 CADENZA Study

Circulating C1q levels in health and disease, more than just a biomarker

C1q is the recognition molecule of the classical pathway of the complement system. By binding to its targets, such as antigen-bound immunoglobulins or C-reactive protein, C1q contributes to the innate defense against infections. However, C1q also plays several other roles beyond its traditional role in complement activation. Circulating levels of C1q are determined in routine diagnostics as biomarker in several diseases.Decreased C1q levels are present in several autoimmune conditions. The decreased levels reflect the consumption of C1q by complement activation and serves as a biomarker for disease activity. In contrast, increased C1q levels are present in infectious and inflammatory diseases and may serve as a diagnostic biomarker. The increased levels of C1q are still incompletely understood but are suggested to modulate the adaptive immune response as C1q is known to impact on the maturation status of antigen-presenting cells and C1q impacts directly on T cells leading to decreased T-cell activity in high C1q conditions.In this review, we provide a comprehensive overview of the current literature on circulating levels of C1q in health and disease, and discuss how C1q can both protect against infections as well as maintain tolerance by regulating adaptive immunity.

Role of uromodulin and complement activation in the progression of kidney disease.

Uromodulin (UMOD) is a glycoprotein that is selectively expressed on the epithelial cells of the thick ascending limb of Henle's loop and the early distal renal tubule. The present study aimed to investigate whether UMOD was associated with complement activation in patients with renal diseases. In addition, its biological function was examined in vitro. The expression levels of UMOD and complement components, including C1q, C3, C4 and C3a, and membrane attack complex (MAC) in the plasma of patients with IgA nephropathy (IgAN; n=58) and lupus nephritis (LN; n=36) were detected using ELISA, which was used to determine the association between UMOD expression and complement components. In addition, a simulated hypoxia-reoxygenation (H/R) model was used to stimulate UMOD expression in mouse inner medullary collecting duct cells. Additionally, the association between UMOD expression and complement components C1q and C3d at the cellular level was identified using western blotting and immunofluorescence, respectively. It was revealed that the plasma UMOD concentration was significantly decreased in patients with IgAN and LN compared with in healthy controls, and the levels of C3a and MAC were significantly increased in the plasma of patients with IgAN and LN. Furthermore, the plasma levels of C1q, C3 and C4 in patients with LN, but not in patients with IgAN, were significantly decreased compared with in healthy controls. The plasma levels of UMOD were negatively correlated with the plasma C3a and MAC concentrations. However, the plasma levels of UMOD were significantly and positively correlated with the plasma C1q concentration, but not with that of C3 and C4. It was identified that UMOD expression started to increase after 1 h of simulated H/R, and continued to increase at 6 and 12 h. In addition, cells with lower UMOD expression had higher C3d expression in vitro. Collectively, the present results suggested that UMOD was associated with severe complement activation and may be involved in complement-mediated immune protection by inhibiting complement activation in renal disease.

Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model.

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.

Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality.

BackgroundThe SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes.MethodsWe conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality.ResultsFour clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group.ConclusionThese findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.

A Preliminary Study of the Complement Component 1q Levels in Predicting the Efficacy of Combined Immunotherapy in Patients with Lung Cancer.

ObjectiveTo evaluate the value of serum complement component 1q (C1q) levels in predicting the efficacy of combined immunotherapy in patients with lung cancer.MethodsA total of 42 patients with lung cancer who received combined immunotherapy in the cancer center of Renmin Hospital of Wuhan University were included in this study. The clinical data of serum C1q and lactate dehydrogenase (LDH) levels before and three weeks after immunotherapy were collected.ResultsResponse evaluation showed that the number of patients with complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 26 (61.9%), 14 (33.3%), and 2 (4.8%), respectively. The CR/PR group (patients with CR or PR) showed higher pC1q (C1q level before immunotherapy) and iC1q (C1q level 3 weeks after immunotherapy) than the SD/PD group (patients with SD or PD). The LDH reduction (96.2%) and C1q increment (84.6%) in the CR/PR group 3 weeks after immunotherapy were higher than those of the SD/PD group, and the differences were statistically significant. Logistic regression analysis indicated that pC1q, iC1q, and LDH level trends 3 weeks after the treatment were significantly correlated to the efficacy of combined immunotherapy with odds ratios of 8.185, 5.500, and 0.031, respectively.ConclusionHigh C1q levels before immunotherapy and increased C1q levels and decreased LDH levels 3 weeks afterward suggest good therapeutic effects of combined immunotherapy in patients with lung cancer. Serum C1q levels have certain clinical significance in predicting the efficacy of combined immunotherapy.

Serum C1q Levels Have Prognostic Value for Sepsis and are Related to the Severity of Sepsis and Organ Damage.

ObjectiveTo explore the clinical application value of serum complement component C1q levels in sepsis.MethodsThe clinical data and laboratory examination data of 320 research subjects (including 132 cases as sepsis group, 93 cases as nonsepsis group and 95 cases as control group) who were diagnosed and treated in Renmin Hospital of Wuhan University from July 2020 to March 2021 were collected. We compared the levels of each index among the three groups and further analyzed the C1q levels of different severity subgroups and different outcome subgroups of sepsis. Afterwards, we explored the correlation between C1q levels and SOFA score, organ damage indexes and coagulation indexes. Finally, the receiver operating characteristic curve (ROC) was used to analyze the prognostic value of C1q in patients with sepsis.ResultsC1q levels were significantly reduced in the serum of patients with sepsis; the level of C1q in the death group was lower than that in the survival group (127.1 mg/L vs 153.2 mg/L, P < 0.05), and the mortality in the C1q decreased group was higher when compared with C1q normal group; in addition, serum C1q levels were correlated with SOFA score, organ damage indexes and coagulation indexes; C1q had a high area under the curve (AUC) for the prognosis of sepsis, and the combination of other indexes can further improve the prognostic value.ConclusionSerum C1q levels have potential clinical value for the condition and prognosis of sepsis.

Larynx Angioedema as a Signal in Chronic Lymphocytic Leukemia: A Case-based Guide for Acquired Angioedema in the Setting of Lymphoproliferative Disorders

ABSTRACT Patients with angioedema can present to the internal medicine, emergency medicine, dermatology, or ear nose throat clinics. Physicians may need to assess the patients whose angioedema is unresponsive to antihistamines systematically in collaboration with other subspecialties including hematology, rheumatology, allergy, and immunology. We aimed to provide a concise review of the diagnosis and multi-disciplinary management of acquired angioedema through a case presentation. A 61-year-old woman presented with recurrent angioedema of 4 episodes within one year. She was evaluated by various disciplines such as dermatology and emergency medicine. Antihistamines and steroids were not effective. The complete blood count (CBC) results indicated lymphocytosis (lymphocyte count=9100 k/μL) and further evaluation of the lymphocytosis with flow cytometry immunophenotyping confirmed a diagnosis of chronic lymphocytic leukemia. Since the acquired angioedema diagnosis was confirmed with low C4, C1q, and C1 esterase inhibitor levels, Rituximab 375 mg/m2 was administered once a week for 4 weeks. The frequency of attacks decreased after rituximab therapy and none of them were life-threatening. In conclusion, when the effective treatment is initiated for the primary diagnosis in acquired angioedema, the numerous emergency department visits, hospitalizations, and the mortality due to life-threatening angioedema episodes can be avoided. Keywords: Angioedema, larynx angioedema, emergency, chronic lymphocytic leukemia, life-threatening angioedema

Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity

BackgroundSynucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer’s disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.MethodsTo investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.ResultsWe demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.Conclusionα-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

Complement activation and increased expression of Syk, mucin-1 and CaMK4 in kidneys of patients with COVID-19

Acute and chronic kidney failure is common in hospitalized patients with COVID-19, yet the mechanism of injury and predisposing factors remain poorly understood. We investigated the role of complement activation by determining the levels of deposited complement components (C1q, C3, FH, C5b-9) and immunoglobulin along with the expression levels of the injury-associated molecules spleen tyrosine kinase (Syk), mucin-1 (MUC1) and calcium/calmodulin-dependent protein kinase IV (CaMK4) in the kidney tissues of people who succumbed to COVID-19. We report increased deposition of C1q, C3, C5b-9, total immunoglobulin, and high expression levels of Syk, MUC1 and CaMK4 in the kidneys of COVID-19 patients. Our study provides strong rationale for the expansion of trials involving the use of inhibitors of these molecules, in particular C1q, C3, Syk, MUC1 and CaMK4 to treat patients with COVID-19.

Integrated Analysis of mRNA and miRNA Changes in Two Haliotis diversicolor Genotypes and Their Hybrid

Heterosis is a widely distributed phenomenon in mollusks. It is vital in aquaculture by bringing beneficial traits into hybrids. People have utilized the heterosis theory in aquaculture for years. However, the molecular basis of heterosis remains elusive. Evident growth and survival heterosis were shown in the hybrid (“Dongyou-1”) of two Haliotis diversicolor geographic genotypes (Japan and Taiwan). To explore the molecular basis underlying the hybrid abalone’s heterosis, we conducted comparative mRNA and miRNA transcriptional analysis in the hybrid and parental genotypes. Differentially expression analysis identified 5,562 differentially expressed genes (DEGs) and 102 differentially expressed miRNAs (DEMs) between the three genotypes. 1,789 DEGs and 71 DEMs were found to be non-additively expressed in the hybrid. Meanwhile, both the expression level dominance pattern (ELD) and expression level overdominance pattern (ELOD) were found in the DEGs and DEMs, showing the existence of dominance and overdominance models in the hybrid’s transcriptome and post-transcriptional regulation. Functional analysis showed the non-additively expressed genes, ELD genes, and ELOD genes were significantly enriched in growth, immunity, and stress response related pathways, while some of the pathways were regulated by the mRNA-miRNA interactions. The expression levels of FGF, C1Q, HC, CAT, SEGPX, and MGST were significantly up-regulated in the hybrid compared to the middle parent value. In conclusion, we identified the existence of non-additivity, dominance, and overdominance models in the transcriptome and miRNAome of the H. diversicolor hybrid; these models facilitate the advantageous parental alleles’ integration into the hybrid, contributing to the hybrid’s growth and survival heterosis.

Novel Monoclonal Antibodies Against Mouse C1q: Characterisation and Development of a Quantitative ELISA for Mouse C1q

Recent studies have identified roles for complement in synaptic pruning, both physiological during development and pathological in Alzheimer’s disease (AD). These reports suggest that C1q initiates complement activation on synapses and C3 fragments then tag them for removal by microglia. There is an urgent need to characterise these processes in rodent AD models; this requires the development of reagents and methods for detection and quantification of rodent C1q in fluids and pathological tissues. These will enable better evaluation of the role of C1q in disease and its value as disease biomarker. We describe the generation in C1q-deficient mice of novel monoclonal antibodies against mouse and rat C1q that enabled development of a sensitive, specific, and quantitative ELISA for mouse and rat C1q capable of measuring C1q in biological fluids and tissue extracts. Serum C1q levels were measured in wild-type (WT), C1q knockout (KO), C3 KO, C7 KO, Crry KO, and 3xTg and APPNL-G-F AD model mice through ageing. C1q levels significantly decreased in WT, APPNL-G-F, and C7 KO mice with ageing. C1q levels were reduced in APPNL-G-F compared to WT at all ages and in 3xTg at 12 months; C3 KO and C7 KO, but not Crry KO mice, also demonstrated significantly lower C1q levels compared to matched WT. In brain homogenates, C1q levels increased with age in both WT and APPNL-G-F mice. This robust and adaptable assay for quantification of mouse and rat C1q provides a vital tool for investigating the expression of C1q in rodent models of AD and other complement-driven pathologies.

Analysis of early predictive value of serum levels of complement C1q, tumor necrosis factor-related Protein 3 and Interleukin-6 in the progression of ischemic stroke.

article: Analysis of early predictive value of serum levels of complement C1q, tumor necrosis factor-related Protein 3 and Interleukin-6 in the progression of ischemic stroke - Minerva Medica 2021 May 14 - Minerva Medica - Journals

Reduced expression of the cell intrinsic clock protein, Bmal1, in myeloid cells accelerates cognitive decline and alters microglial function in aging mice

The circadian clock system plays a fundamental role in the temporal coordination of the external environment with internal physiological processes. These processes include the sleep/wake cycle, feeding, liver function, kidney function, core body temperature, including insulin release and heart rate, and immune function. With aging, the ability to rhythmically regulate these processes progressively declines. Furthermore, aging is associated with a chronic inflammation that is linked to multiple age-associated diseases, including cognitive decline. Several studies have demonstrated that deletion of Bmal1, a transcription factor and principal driver of cell-autonomous circadian rhythms, accelerates the aging process, exhibiting a variety of age-related diseases including sarcopenia, cataracts, organ shrinkage, bone calcification, and impaired glucose metabolism. Here, we show that myeloid-lineage specific knockdown of Bmal1 increases systemic inflammation and accelerates cognitive decline in aging mice. This was associated with a paradoxical increase in IBA1 expression and number of microglia with less morphological complexity and reduced lysosomal CD68 in the CA1 hippocampal region. Looking at individual microglia showed less CD68 in the Bmal1-deficient microglia, suggesting lysosomal dysfunction. Furthermore, myeloid Bmal1 deletion led to significant increases in pre- and post-synaptic proteins in aged mice, as well as decreased levels of C1q, which is required for synaptic pruning, suggesting impaired synapse clearance. In summary, our data indicates that Bmal1 knock-down in myeloid-lineage cells is sufficient to accelerate cognitive decline by a mechanism that may involve impaired synapse removal.