The complement cascade repurposed in the brain

Object. Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. Erythrocyte lysis may be mediated by the complement cascade, which then triggers parenchymal injury. In this study the authors examine whether the complement cascade is activated after ICH and whether inhibition of complement attenuates brain edema around the hematoma.Methods. This study was divided into three parts. In the first part, 100 µl of autologous blood was infused into the rats' right basal ganglia, and the animals were killed at 24 and 72 hours after intracerebral infusion. Their brains were tested for complement factors C9, C3d, and clusterin (a naturally occurring complement inhibitor) by using immunohistochemical analysis. In the second part of the study, the rats were killed at 24 or 72 hours after injection of 100 µl of blood. The C9 and clusterin proteins were quantitated using Western blot analysis. In the third part, the rats received either 100 µl of blood or 100 µl of blood plus 10 µg of N-acetylheparin (a complement activation inhibitor). Then they were killed 24 or 72 hours later for measurement of brain water and ion contents. It was demonstrated on Western blot analysis that there had been a sixfold increase in C9 around the hematoma 24 hours after the infusion of 100 µl of autologous blood. Marked perihematomal C9 immunoreactivity was detected at 72 hours. Clusterin also increased after ICH and was expressed in neurons 72 hours later. The addition of N-acetylheparin significantly reduced brain edema formation in the ipsilateral basal ganglia at 24 hours (78.5 ± 0.5% compared with 81.6 ± 0.8% in control animals, p < 0.001) and at 72 hours (80.9 ± 2.2% compared with 83.6 ± 0.9% in control animals, p < 0.05) after ICH.Conclusions. It was found that ICH causes complement activation in the brain. Activation of complement and the formation of membrane attack complex contributes to brain edema formation after ICH. Blocking the complement cascade could be an important step in the therapy for ICH.

Download Full-text

Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat

Journal of Neurosurgery ◽

10.3171/jns.1996.85.3.0468 ◽

1996 ◽

Vol 85 (3) ◽

pp. 468-475 ◽

Cited By ~ 78

Author(s):

Bo-Michael Bellander ◽

Hans von Holst ◽

Pam Fredman ◽

Mikael Svensson

Keyword(s):

Traumatic Injury ◽

Complement Cascade ◽

Complement Factor ◽

Survival Times ◽

Adult Rats ◽

Content Type ◽

Junction Protein ◽

Cortical Contusion ◽

The Brain ◽

Fine Print

✓ The aim of the present study was to examine the glial cell response and the possible involvement of the complement cascade following a cerebral cortical contusion. The lesion was produced using a standardized weight-drop technique in adult rats. The blood-brain barrier was damaged, as demonstrated by a decrease of immunoreactivity for a tight junction protein normally expressed by endothelial cells of small vessels in the central nervous system. Increased immunoreactivity for microglial (OX42) and astroglial cells (glial fibrillary acidic protein), as well as macrophages expressing ED1-immunoreactivity (IR) were found in the vicinity of the lesion at all postoperative survival times (2–14 days). In the present study complement factor C3d- and C9-IR was found around the lesion, indicating that activation of the complement cascade had taken place. Furthermore, immunoreactivity for the putative complement inhibitor clusterin (sulfated glycoprotein-2) was found in some of the injured neurons. The contralateral hemisphere showed no evidence of the reaction found in the ipsilateral hemisphere. The balance between complement activation and complement inhibitors may have an impact on the degenerative components in the brain following traumatic injury and in particular on the events leading to nerve cell death.

Download Full-text

Exercise conditioned plasma dampens inflammation via clusterin and boosts memory

10.1101/775288 ◽

2019 ◽

Cited By ~ 2

Author(s):

Zurine De Miguel ◽

Michael J. Betley ◽

Drew Willoughby ◽

Benoit Lehallier ◽

Niclas Olsson ◽

...

Keyword(s):

Gene Expression ◽

Cognitive Aging ◽

Animal Health ◽

Brain Inflammation ◽

Cognitively Impaired ◽

Complement Cascade ◽

Striking Increase ◽

Cognitive Benefits ◽

Anti Inflammatory ◽

The Brain

Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered “runner” plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and prominently suppresses experimentally induced brain inflammation. Plasma proteomic analysis shows a striking increase in complement cascade inhibitors including clusterin, which is necessary for the anti-inflammatory effects of runner plasma. Cognitively impaired patients participating in structured exercise for 6 months showed higher plasma clusterin levels, which correlated positively with improvements in endurance and aerobic capacity. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, benefit the brain, and are present in humans engaging in exercise.

Download Full-text

Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity

10.1101/2020.02.03.931949 ◽

2020 ◽

Author(s):

Leah C. Graham ◽

Heidi E. Kocalis ◽

Ileana Soto ◽

Gareth R. Howell

Keyword(s):

White Matter ◽

Mouse Model ◽

Cognitive Decline ◽

Western Diet ◽

Complement Component ◽

Complement Cascade ◽

Brain Pathology ◽

White Matter Damage ◽

Diet Induced Obesity ◽

The Brain

ABSTRACTAge-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity induced brain pathology, female and male mice deficient in complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared to WD-fed WT mice, and to C1qa knockout (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.SIGNIFICANCE STATEMENTEconomic growth, an increasingly sedentary lifestyle and a nutritional transition to processed foods and high calorie diets have led to a significant increase in obesity prevalence. Several chronic diseases have been associated with obesity, including dementia. Obesity-induced, peripheral inflammation has been proposed as a possible trigger of pathological changes in the brain that lead to cognitive dysfunction and predisposition to dementia. Here we show that genetic deletion of the complement component C1QA prevents cerebrovascular damage, neuroinflammation and white matter degradation in a mouse model of western diet-induced obesity, demonstrating that inflammatory responses play a significant role in obesity-induced brain pathology. The complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity.

Download Full-text

Evidence for Alternative Complement Cascade Activation in Primary CNS Vasculitis

10.1101/329862 ◽

2018 ◽

Author(s):

Caleigh Mandel-Brehm ◽

Hanna Retallack ◽

Giselle M. Knudsen ◽

Alex Yamana ◽

Rula A. Hajj-Ali ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Physiological Activity ◽

Therapeutic Interventions ◽

Complement Cascade ◽

Cns Vasculitis ◽

Alternative Complement ◽

Primary Angiitis ◽

The Central Nervous System ◽

The Brain

AbstractThe central nervous system (CNS) has a dedicated network of blood vessels to support the physiological activity of the brain, spinal cord and meninges. Consequently, inflammation of CNS vasculature can have devastating effects on neurological function. A lack of understanding regarding the molecular pathology of CNS vasculitis impedes the development of better diagnostics and effective therapies. Here, we analyze the proteome of cerebrospinal fluid from patients with biopsy-confirmed Primary Angiitis of the Central Nervous System (PACNS) relative to non-inflammatory control patients and patients with Reversible Cerebral Vasoconstrictive Syndrome (RCVS), a syndrome that clinically mimics PACNS in several aspects. In PACNS, we find significant elevation of apolipoproteins, immunoglobulins and complement cascade components. Notably, we find a bias towards activation of the alternative complement pathway with elevated levels of the terminal cascade component, complement C5. Given the recent treatment successes of Anti-Neutrophil Cytoplasmic Antibody (ANCA) vasculitis with the C5 receptor inhibitor, CCX168 (Avacopan), our results suggest that complement C5 inhibitors may also prove useful as therapeutic interventions for PACNS.

Download Full-text