Astrocytes, which are brain cells, regulate the immune response and inflammatory environment in the brain by secreting immune proteins like C4. As a result, astrocytes are the principal target of C4-lowering therapy.
There is a strong rationale for targeting the complement system as a therapeutic approach to improving brain function. Genetic variations in complement component 4 (C4) copy number have been linked to the increased risk of schizophrenia. In addition, schizophrenia patients exhibit elevated C4 expression in the cerebral cortex.
Although the exact mechanism underlying schizophrenia is unknown, C4 over-expression can lead to reduced thickness and synaptic density in the brain cortex of patients with schizophrenia.
Astrocytes in Brain and Schizophrenia
Astrocytes play a critical role in synapse formation, function, and elimination The contribution of astrocytes to neuropsychiatric and neurodegenerative diseases has been increasingly recognized. Astrocytes and microglia are considered the immune cells of the brain due to their ability to secrete chemokines and cytokines, complement proteins, and for their phagocytic function. In particular, astrocytes express and secrete complement components, such as C1r, C1s, C2, C3, and C4, which, therefore, may act cell non-autonomously.
Importance of Complement System
The complement system is part of the first line of defense against harmful pathogens. While the primary site of complement synthesis is the liver, production of complement also happens in the central nervous system (CNS).
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In addition to its role in CNS inflammation, the complement system shapes the developing brain by controlling synaptic refinement to ensure proper brain function. In the mature human brain, aberrant activation of the complement has been observed in the CNS of patients with neurodegeneration, autoimmune diseases, and aging.
Excessive complement activation gives rise to early synaptic loss, correlating with cognitive impairment in Alzheimer’s disease (AD) and Tauopathy. Blocking the complement system in vivo rescues aberrant synaptic pruning and attenuates neuroinflammation and neurodegeneration in mouse models of AD.
This study opens up new avenues for studying inflammatory responses and their regulation in human astrocytes and serves as a platform to identify therapeutic drugs in large-scale screening approaches.
Reference :
- Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes
– (https:pubmed.ncbi.nlm.nih.gov/36563689/)
Source: Medindia
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