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HomeGeneralThe Guardian of the Brain - Microglia.

The Guardian of the Brain – Microglia.

In mammalian brains, neurons are often considered the most abundant cells, but in reality, they are far outnumbered by another type of cell: glial cells. Glial cells account for about 90% of the total cellular content in the brain, with microglia making up about 20% of this glial population. Despite their smaller proportion, microglia play a crucial role in maintaining the tissue homeostasis of the central nervous system (CNS). Microglia are the primary immune cells of the CNS, and their functions extend beyond immune responses in diseases. They dynamically interact with neurons in the adult brain. In a healthy brain, homeostatic microglia physically interact with various parts of neurons, such as the neuronal soma, axon initial segment, nodes of Ranvier, and synapses, to shape neural structures and regulate neuronal activity.

During brain development, microglia help form neural circuits by participating in synaptic pruning and promoting synapse formation. In the adult CNS, neuronal circuits undergo significant regulation and remodeling. Microglia can also sense and regulate neuronal activity through synaptic interactions. Excessive neuronal excitation can lead to abnormal behaviors or physiological activities, such as epilepsy. When neurons are overly excited, microglia enhance their interaction with neurons to reduce neuronal firing. Conversely, when neurons are in a low-activity state, such as when an animal is under anesthesia, microglia can block inhibitory synaptic signals to promote neuronal activity. Overall, through their dynamic interactions with neurons, microglia maintain brain homeostasis and achieve a balance in neuronal activity.

Additionally, microglia can regulate neuronal regeneration and synaptic plasticity. Thus, they are indispensable for the formation of neural networks and the proper functioning of various behaviors in animals.

In recent years, clinical studies have shown that certain overactivated phenotypes of microglia can lead to CNS diseases, such as neuronal dysfunction, damage, and degeneration. Microglia play a significant role in cerebrovascular diseases, neurodegenerative diseases, neurodevelopmental disorders, and psychiatric illnesses, making them a hot topic in neuroscience and translational medicine research. Currently, research on microglia largely relies on constructing transgenic mouse models to introduce exogenous genes or genetic modifications into microglia. However, this method is time-consuming, labor-intensive, costly, and not translatable into practical therapeutic strategies. Among various viral vectors, recombinant adeno-associated viruses (rAAV) are widely used as tracing tools and gene therapy delivery vectors in neuroscience research due to their high safety. The diverse serotypes of rAAV grant them various tissue-targeting infection properties. However, AAV vectors that allow efficient and specific transduction of microglia are relatively rare.

In July 2024, a team led by Fuqiang Xu and Kunchang Lin from the Chinese Academy of Sciences and their translational platform Brain Case Biotech published a preprint on BioRxiv titled “Microglia-specific transduction via AAV11 armed with IBA1 promoter and miRNA-9 targeting sequences.” The study reported on the specificity and efficiency of various AAV vectors carrying the mIBA1 promoter and miRNA-9 targeting sequences in transducing microglia in the caudate putamen (CPu) brain region. They found that AAV11 mediated more specific and efficient transduction of microglia, and AAV11 also exhibited high transduction specificity for microglia in different brain regions and the spinal cord. This work provides a powerful tool for microglia research and offers a feasible approach for targeted therapy of microglia-related CNS diseases.

Figure. AAV11(a type of virus vectors) sparsely labels microglia

Brain Case Biotech has made significant strides in the field of microglia research, particularly with their development of AAV11 vectors for specific and efficient transduction of microglia. This breakthrough opens up several promising avenues for future research and therapeutic applications:

  1. Targeted Gene Therapy: The ability to specifically target microglia with AAV11 vectors carrying therapeutic genes could lead to innovative treatments for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, where microglial dysfunction plays a critical role. This approach could also be applied to other CNS disorders like multiple sclerosis and amyotrophic lateral sclerosis (ALS).
  2. Understanding Microglial Functions: With the improved tool for specifically targeting microglia, researchers can gain deeper insights into the diverse roles of microglia in the CNS. This includes their involvement in synaptic pruning, neuroinflammation, and their interactions with other neural cells. Such understanding could unveil new therapeutic targets and strategies.
  3. Drug Development: The high specificity of AAV11 vectors for microglia provides a robust platform for screening and validating new drugs targeting microglial pathways. This could accelerate the development of drugs aimed at modulating microglial activity to treat various CNS diseases.
  4. Investigating Microglial Heterogeneity: The ability to transduce microglia in specific brain regions allows for the study of regional differences in microglial function and phenotype. This could lead to the discovery of region-specific therapeutic strategies and a better understanding of how microglia contribute to different CNS pathologies.
  5. Gene Editing and RNA Interference: AAV11 vectors can be used to deliver CRISPR/Cas9 or RNA interference molecules specifically to microglia. This capability allows for precise manipulation of gene expression within microglia, facilitating the study of gene function and the development of gene-based therapies.
  6. Microglia in Developmental and Psychiatric Disorders: Research into how microglia contribute to neurodevelopmental and psychiatric disorders, such as autism spectrum disorders and schizophrenia, can benefit from the specific targeting capabilities of AAV11. This could lead to novel insights and therapeutic approaches for these conditions.
  7. Collaborative Research and Innovation: Brain Case Biotech’s advancements are likely to foster collaborations with academic institutions, pharmaceutical companies, and biotech firms. Such collaborations could accelerate the translation of these research findings into clinical applications.

Future Directions

  1. Optimization and Validation: Continued optimization of AAV11 vectors to enhance their efficiency and specificity across different microglial populations and CNS regions will be crucial. Extensive validation in various animal models and eventually in human studies will be necessary.
  2. Exploring Combinatorial Therapies: Combining microglia-targeted gene therapy with other treatments, such as anti-inflammatory drugs or neuroprotective agents, could provide synergistic effects and improve therapeutic outcomes for complex CNS diseases.
  3. Developing Non-Invasive Delivery Methods: Innovations in delivery methods that minimize invasiveness, such as advanced imaging-guided injections or blood-brain barrier-penetrating techniques, will enhance the clinical applicability of these therapies.
  4. Regulatory and Ethical Considerations: Addressing regulatory and ethical issues related to gene therapy and the use of viral vectors in humans will be essential to ensure the safe and effective translation of these technologies into clinical practice.

Brain Case Biotech is well-positioned to lead the way in microglia research, with the potential to make significant contributions to neuroscience and the treatment of CNS diseases.

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