What role do microglia play in neurodegeneration?

The Complex Role of Microglia in Neurodegeneration

Microglia in neurodegenerative disorders display a heterogeneous range of states with diverse functions that can be both neuroprotective and neurotoxic, making them critical mediators in the progression of neurodegeneration through their roles in phagocytosis, synaptic modification, and neuroinflammation. 1

Microglial Functions in Neurodegeneration

Dual Nature of Microglial Activity

• Microglia serve as the brain's resident immune cells that defend against injury and pathogens, clear toxic proteins, and promote neurogenesis, but hyper-reactive microglia can lead to chronic inflammation associated with neurodegeneration 1
• The historical oversimplification of microglial activities into "good vs. bad" or "protective vs. harmful" fails to capture their complex biology in neurodegenerative processes 1
• Recent research using human stem cell-derived microglia xenotransplantation models reveals microglia exist in multiple states: homeostatic, cytokine response-1 and -2, interferon response, disease-associated response, and antigen-presenting response 1

Phagocytic Function

• In neurodegenerative disorders, microglia can initiate phagocytosis to clear pathological protein aggregates, but excessive uptake can lead to impaired phagocytic ability and accelerated neurodegeneration 2
• Microglia are key regulators of activity-dependent circuit refinement through the complement cascade, which is critical for normal development but may be aberrantly activated in disease states 1
• The complement pathway activation via C3 can prime microglia toward a cytotoxic state in neurodegenerative contexts 1

Neuroinflammatory Processes

• Activated microglia can release potentially cytotoxic molecules including proinflammatory cytokines, reactive oxygen intermediates, proteinases, and complement proteins that contribute to neuronal damage 3
• Exposure to effectors like IL-4/IL-13 can transition microglia in vitro from a homeostatic to a cytotoxic phenotype, altering their functional state in disease 1
• Chronic activation of microglia creates a feedback loop where factors secreted by dead or dying neurons further exacerbate microglial activation, causing progressive neuronal loss 4

Microglial States in Disease

Disease-Specific Responses

• Microglia display differential responses to specific pathologies and genetic risk factors across various neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, and Huntington's disease 1, 2
• In Alzheimer's disease, consideration of microglial subpopulations/states and genetic drivers is critical to understanding their impact across the pathological continuum 1
• Microglia can act as mobile vehicles to propagate protein aggregates, and their extracellular vesicles contribute to pathological progression 2

Interaction with Other Cell Types

• Microglia interactions with astrocytes can trigger functional conversion of astrocytes from neurotrophic to neurotoxic, amplifying neurodegeneration 1
• The interplay between microglia and peripheral immune cells that infiltrate the CNS can shape microglia into a pro-inflammatory phenotype, accelerating disease progression 2
• Future models of neurodegeneration will require co-culture with microglia to develop therapeutic approaches that aim to restore normal microglial function 1

Challenges in Studying Microglial Contribution to Neurodegeneration

Measurement and Interpretation Issues

• Single inflammatory markers should not be interpreted in isolation as an overall index of immune biology in neurodegenerative diseases 1
• CSF markers often used to model immune cell activation may not accurately reflect the complex cellular changes occurring in the brain parenchyma 1
• Parenchymal glia secretome is likely insufficiently and non-uniformly captured by bulk CSF assays, limiting our ability to directly correlate CSF findings with brain pathology 1

Emerging Research Approaches

• Network-level assessment of immune cells and inflammatory markers provides a better window into the changing immune ecosystem that intersects with neurodegenerative diseases 1
• Development of protocols to reproducibly generate microglia from human iPSC lines is providing relevant sources for studying microglial biology in neurodevelopmental and neurodegenerative diseases 1
• Future research should focus on microglial subpopulations/states and genetic drivers to better understand their temporal and spatial contributions to disease progression 1

Therapeutic Implications

• Enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis/secretion, and promoting conversion to protective phenotypes are promising strategies for neurodegenerative disease therapy 2
• Suppression of microglia-mediated inflammation has been considered an important strategy in neurodegenerative disease therapy, with several anti-inflammatory drugs showing potential to repress microglial activation 3
• Resolving chronic inflammation mediated by microglia bears promise as a novel treatment strategy to reduce neuronal damage and foster a permissive environment for regeneration 4