The complement system is activated by the classical, lectin, or alternative pathways. tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical Mouse monoclonal to MLH1 complement pathway, that are independent of the rest of the complement cascade, as well Mcl-1 antagonist 1 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 Mcl-1 antagonist 1 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, Alzheimers 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 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]). Perhaps due to the ancient evolutionary origins of the pathway, it may not Mcl-1 antagonist 1 be surprising that in the past 15 years, multiple noncanonical Mcl-1 antagonist 1 functions of complement have been uncovered (reviewed in [2]). Complement is activated by three different recognition pathways (classical, alternative, and lectin), all of which lead to sequential enzyme activation, protein cleavage, and induced function-enabling protein conformational changes (Fig. ?(Fig.1).1). The classical complement pathway is activated when the C1 complex (C1q, C1r2, and C1s2) binds, via the C1q subcomponent, to the Fc domain of antibody in immune complexes or to nonimmunoglobulin activators such as apoptotic cells, or other polyanionic substances including fibrillar A? [3] and hyperphosphorylated tau ( [4] and reviewed in [5]). This binding induces the autoactivation of the proenzyme C1r which then cleaves and activates C1s, another serine protease. Activated C1s cleaves component C4, generating C4a and C4b. C4b covalently attaches to the activator surface and recruits C2. C1s then cleaves C2 into C2a and C2b. C4b and C2b form the C3 convertase (C4b2b), which can sequentially cleave multiple C3 proteins into C3a and C3b. C3b also covalently attaches to the surface, providing the opsonic signal to phagocytes for ingestion (and subsequent killing or degradation). Some of the cleaved C3b remains associated with the C4b2b forming C4b2b3b, the classical pathway C5 convertase. The C5 convertase then cleaves C5 into C5a and C5b. C5b initiates the formation of the pore-forming C5b, C6, C7, C8, and C9 complex (C5b-9). The lectin pathway is quite similar to the classical pathway except that the recognition components, mannan-binding lectin (MBL), ficolins and collectins, and the MBL-associated serine proteases, MASP1/2, are activated by interaction with specific carbohydrate structures (not normally present in the host). Once activated, MASP1/2 cleaves C4 and C2 thereby forming the C3 cleaving enzyme (C4b2b) and enabling subsequent steps in the cascade. The alternative pathway of activation is the result of the direct attachment of cleaved C3b to a permissive/acceptor surface, which is often a pathogen but can also be other surfaces, ultimately resulting in the generation of the C3 cleaving enzyme complex C3bBb and the alternative C5 cleaving enzyme C3bBb3b [6] (Fig. ?(Fig.11)..