The loss of synapses is an early hallmark of Alzheimer's disease (AD) preceding neuronal loss and predicting cognitive deficit. Dr Ben Bares, Annexon co-founder, has determined that the classical complement protein C1q, which is up regulated ~70 fold in the AD brain, is a critical mediator of synapse loss in the nervous system. Moreover genetic ablation of C1q was shown to be protective in rodent models for AD, glaucoma, and stroke and related complement pathway genes were recently shown to be associated with susceptibility to AD. The goal of this Phase 1 proposal is to identify monoclonal antibodies that inhibit C1q and its associated protein C1s and prepare them for testing in animal models of AD. Specifically, we are using mouse hybridoma and phage display to isolate antibodies that bind C1q and C1s. These antibodies will then be tested for their ability to inhibit the activity of mouse and human C1q and C1s using in vitro assays of complement function. Phase II of the project will evaluate the therapeutic potential of these inhibitors in mouse models of AD. Demonstration of a therapeutic effect in mice will provide a rationale for clinical development of these antibodies.
Public Health Relevance: Synapse loss is a hallmark of Alzheimer's disease (AD). It precedes neuronal cel los and predicts cognitive deflect. The classical complement pathway proteins are up-regulated ~10 fold in the aging brain and ~70 fold the brains of Alzheimer's patients. Moreover, this pathway was recently shown to be required for the elimination of synapses in normal mice and mice in which classical complement genes were genetically ablated are partially resistant to Alzheimer's disease. We are developing pharmacological inhibitors of the classical complement cascade and will test them in animal models of AD.
Public Health Relevance Statement: Synapse loss is a hallmark of Alzheimer's disease (AD). It precedes neuronal cel los and predicts cognitive deflect. The classical complement pathway proteins are up-regulated ~10 fold in the aging brain and ~70 fold the brains of Alzheimer's patients. Moreover, this pathway was recently shown to be required for the elimination of synapses in normal mice and mice in which classical complement genes were genetically ablated are partially resistant to Alzheimer's disease. We are developing pharmacological inhibitors of the classical complement cascade and will test them in animal models of AD.
NIH Spending Category: Aging; Alzheimer's Disease; Biotechnology; Brain Disorders; Neurodegenerative; Neurosciences; Prevention
Project Terms: Ablation; Adult; aging brain; Alzheimer's Disease; Animal Model; Antibodies; Antibody Formation; Binding (Molecular Function); Biological Assay; Blocking Antibodies; Brain; Classical Complement Pathway; Clinical; Clinical Research; Cognitive; Cognitive deficits; Complement; Complement 1q; Complement Activation; Complement component C1s; Complement Hemolytic Activity Assay; Complement Inactivators; complement pathway; Conditioned Culture Media; Cytolysis; Development; Embryonic Development; Enzyme-Linked Immunosorbent Assay; Enzymes; Epitopes; Erythrocytes; Generations; Genes; Genetic; Genetic Polymorphism; Genome; Glaucoma; Goals; Hemolysis; Human; humanized antibody; Hybridomas; Immune system; Immunization; in vitro activity; in vitro Assay; in vivo; inhibitor/antagonist; Knockout Mice; Measures; Mediating; Mediator of activation protein; Monoclonal Antibodies; mouse model; Mus; Nervous system structure; neuron loss; Neurons; novel; Pathway interactions; Patients; Peptides; Phage Display; Phase; Plasma; Play; Predisposition; prevent; Procedures; Production; Protein Isoforms; Proteins; research study; Resistance; Rodent Model; Screening procedure; site-specific integration; stable cell line; stroke; Surveys; Synapses; Technology; Testing; Therapeutic; Therapeutic Effect; Work
