B. Paul Morgan
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View article: Complement gene expression profiles are altered in the AD frontal cortex
Complement gene expression profiles are altered in the AD frontal cortex Open
Background Complement contributes significantly to pathophysiology in many neurodegenerative diseases (NDDs) including Alzheimer's Disease (AD); yet, the source of complement in the brain is poorly understood. Even multiple small changes t…
View article: Absence of complement terminal pathway activity in C6-deficient mice prolongs survival in a mouse model of severe malarial infection
Absence of complement terminal pathway activity in C6-deficient mice prolongs survival in a mouse model of severe malarial infection Open
We show that complement terminal pathway activation exacerbates organ injuries and thrombocytopenia associated with P. bergei infection, contributing to rapid progression to death in the model. Inhibition of terminal pathway activation in …
View article: Platelets Link Coagulation and Complement in Regulating Placental Vascular Development
Platelets Link Coagulation and Complement in Regulating Placental Vascular Development Open
During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential st…
View article: The Alzheimer's disease‐associated complement receptor 1 variant confers risk by impacting glial phagocytosis
The Alzheimer's disease‐associated complement receptor 1 variant confers risk by impacting glial phagocytosis Open
INTRODUCTION Genome‐wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35), confers increased AD risk. We confirmed CR1 expression on glial cells; however, ho…
View article: <scp>CD59</scp>, Disulphide‐Locked Human <scp>C9</scp> and Horse <scp>C9</scp> Inhibit Human Membrane Attack Complex Assembly by Similar Mechanisms
<span>CD59</span>, Disulphide‐Locked Human <span>C9</span> and Horse <span>C9</span> Inhibit Human Membrane Attack Complex Assembly by Similar Mechanisms Open
Five plasma proteins, C5b, C6, C7, C8 and C9, assemble in a step‐wise manner to form the membrane attack complex (MAC) which inserts into target cell membranes to cause lysis. The membrane regulator CD59 binds nascent C5b‐8, preventing C9 …
View article: Complement dysregulation in human tauopathies
Complement dysregulation in human tauopathies Open
Dysregulation of the complement system plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In post‐mortem AD brains, complement is deposited in and around amyloid plaques, and peri…
View article: Inhibition of terminal complement complex formation alleviates murine antibody-mediated TRALI
Inhibition of terminal complement complex formation alleviates murine antibody-mediated TRALI Open
Transfusion-related acute lung injury (TRALI) is a leading cause of blood transfusion–triggered mortality. Recently, we demonstrated the critical role of Fc-dependent complement activation in anti-CD36–mediated murine TRALI. In this study,…
View article: Complement biosynthesis in human brain: Insights from single-nucleus transcriptomics of hippocampus
Complement biosynthesis in human brain: Insights from single-nucleus transcriptomics of hippocampus Open
Complement is a key contributor to neuroinflammation, driving pathology in neurodegenerative diseases (NDDs); however, little is known about the source of complement in brain. Effective targeting of complement in NDDs requires understandin…
View article: A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin
A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin Open
Aficamten (CK-3773274) is a cardiac myosin inhibitor in development for the treatment of hypertrophic cardiomyopathy (HCM), a commonly inherited heart condition often characterized as a disease of the sarcomere. Aficamten reduces pathologi…
View article: Plasma complement system markers and their association with cardiometabolic risk factors: an ethnic comparison of White European and Black African men
Plasma complement system markers and their association with cardiometabolic risk factors: an ethnic comparison of White European and Black African men Open
The present study found that markers of the complement system were less strongly associated with adiposity and lipid profiles in Black African men compared with White European men, suggesting ethnic differences in the determinants of compl…
View article: Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation
Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation Open
Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor ( Csf1r) gene ( Csf1rko ) severely compromises pre-w…
View article: Targeting novel anti‐complement drugs to the brain reduces complement activation and synapse loss, and improves cognition in a mouse model of dementia
Targeting novel anti‐complement drugs to the brain reduces complement activation and synapse loss, and improves cognition in a mouse model of dementia Open
Background In the brain as in other organs, complement contributes to immune defence and housekeeping to maintain homeostasis. Sources of complement may include local production by brain cells and influx from the periphery, the latter seve…
View article: Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia
Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia Open
Background Neuroinflammation is a critical factor of Alzheimer’s Disease (AD). Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in th…
View article: Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer’s disease mouse model
Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer’s disease mouse model Open
Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury in Alzheimer’s disease and other neurodegenerative diseases. Here, we investigate the impact of brain delivery of a complement-bl…
View article: Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility
Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility Open
Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for …