The good, the bad, and the opportunities of the complement system in neurodegenerative disease
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(2020) 17:354
REVIEW
Open Access
The good, the bad, and the opportunities of the complement system in neurodegenerative disease Nicole D. Schartz1 and Andrea J. Tenner1,2,3*
Abstract The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease. Keywords: Complement, Neurodegeneration, Neuroprotection, Alzheimer’s disease, Toll-like receptors, Microglia, Multiple sclerosis, Epilepsy, Traumatic brain injury, Stroke
Complement Complement cascade
Over 40 proteins are involved in the complement system, a part of the innate immune response which is critical for quickly recognizing and clearing pathogens, apoptotic cells, and cellular debris prior to generation of * Correspondence: [email protected] 1 Department of Molecular Biology and Biochemistry, University of California Irvine, 3205 McGaugh Hall, Irvine, CA 92697, USA 2 Department of Neurobiology and Behavior, University of California Irvine, 3205 McGaugh Hall, Irvine, CA 92697, USA Full list of author information is available at the end of the article
the adaptive immune system pathogen-specific response or cascading tissue-damaging inflammation. The system is also a dominant participant in antibody-mediated pathogen killing and clearance and contributes to directing the type and extent of the adaptive response (reviewed in [1]).
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