Neurology

As an essential part of the immune system, the complement system has traditionally been considered as a first defense line of innate immunity against invading pathogenesis. However, over the past few decades, several additional roles have been uncovered including the elimination of immune complex, removal of apoptotic cells and debris, modulation of metabolic and regenerative processes, and regulation of adaptive immunity. Complement is activated through one or more of three pathways: the classical, lectin, or alternative pathway and it is regulated tightly by several mechanisms to prevent host injury.

In the central nervous system (CNS), complement proteins can be induced in all cell types and play similar roles in host defense. There are several lines of evidence indicating that the pathogenesis of CNS diseases is closely related to over-activation and/or under-regulation of complement. There are several physiological roles of complement in the CNS:

Sensor and Orchestrator of the Innate Immune Response

Microglia and astrocyte are acknowledged primary immune cells of the CNS, which can utilize the components of complement system to provide the brain with immune sensors and response capabilities. C1q, the initiating protein of the classical complement cascade, has been observed to bind to apoptotic cells, including neurons, and then mediates damaged or dying neurons to be cleared by microglia, thus prevents the release of toxic components to avoid additional insult or injury. In addition to its historic role in recognizing foreign materials and initiating of complement activation, C1q has also been shown to be produced in neurons to play a direct protective role by enhancing the clearance of apoptotic cells. Inflammation and neurodegeneration in Alzheimer’s disease (AD) are partially mediated by complement activation.

Beyond Immune Surveillance

The microglia in CNS can response to C5a stimulation, thus upregulate the glutamate transporter, GLT-1, and increase glutamate uptake which may provide protection against glutamate-mediated excitotoxicity. C5a has also been observed to provide direct protection to differentiated SH-SY5Y neuroblastoma cells against β-amyloid. Complement components have also been evaluated to take part in multiple physiological processes including the developmental refinement of synapses within the visual system.

Neuropathogenic Mediator in Numerous CNS Disease States

C5a has the potential neuroprotective activities, which can activate CD88 to play a deleterious role in CNS disease. Besides AD, several neurodegenerative diseases, such as Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) all seem to indicate C5a induced CD88 activation as a driver of CNS pathology.

Fig. 1 Crucial role of complement in the pathogenesis of various CNS diseases. (Schartz et al., 2020)

Fig. 1 Crucial role of complement in the pathogenesis of various CNS diseases.1

As an important factor in the pathogenesis of numerous diseases of the CNS, including infection, autoimmune and degenerative disorders, neuropsychiatric disease, the complement system has been developed to the potential biomarkers and new drugs targets.

Creative Biolabs provides a series of therapeutic antibodies, inhibitors, soluble complement regulators, as well as customized services to promote the drug development of the complement-associated neurology, such as:
Complement therapeutics for Alzheimer's disease

Our comprehensive complement platform offers a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.

Reference
1. Schartz, Nicole D., and Andrea J. Tenner. "The good, the bad, and the opportunities of the complement system in neurodegenerative disease." Journal of neuroinflammation 17.1 (2020): 1-25.

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Questions & Answer

A: The complement system is part of the immune system and plays a crucial role in neuroinflammation and synaptic pruning in the central nervous system. Dysregulation of the complement system is associated with a variety of neurological disorders, making it a potential target for therapeutic intervention. In neurology, the classical and alternative complement pathways are most relevant. Therapeutic strategies usually focus on inhibiting key complement proteins such as C1q, C3, and C5 to reduce neuroinflammation and synaptic loss.

A: Complement therapeutics can help maintain blood-brain barrier integrity by reducing complement-mediated damage. This, in turn, limits the entry of immune cells and inflammatory mediators into the brain, preserving neurological function.

A: Complement therapeutics can potentially mitigate synaptic dysfunction by preventing excessive complement activation, which is implicated in synaptic pruning. This approach may help preserve synaptic integrity and cognitive function.

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