Microglia play a crucial role in the brain's immune response and are implicated in various neurodegenerative diseases. Recent studies have highlighted their dual role as both protective and pathogenic agents. For instance, research demonstrated that microglia depletion exacerbates demyelination and impairs remyelination during neurotropic coronavirus infection, indicating their essential role in myelin repair (ref: Sariol doi.org/10.1073/pnas.2007814117/). Additionally, the characterization of brain-derived extracellular vesicles (EVs) showed that they are vital for intercellular communication and may influence microglial activation and response to injury (ref: Brenna doi.org/10.1080/20013078.2020.1809065/). Furthermore, the study of the protective Plcγ2-P522R variant revealed that microglial-specific genetic variants can modulate immune functions, suggesting a potential therapeutic target for Alzheimer's disease (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). The interplay between microglial activation and neuroinflammation is further complicated by factors such as aging, where endothelial C3a receptor-mediated vascular inflammation and blood-brain barrier permeability are observed (ref: Propson doi.org/10.1172/JCI140966/). Overall, these findings underscore the importance of microglial function in neuroinflammation and their potential as therapeutic targets in neurodegenerative diseases.

Alzheimer's disease (AD) mechanisms are multifaceted, involving genetic, inflammatory, and metabolic factors. A pivotal study utilized multi-omic approaches to analyze human embryonic stem cell-derived microglia, revealing that variants in genes such as SORL1 and TREM2 converge on the up-regulation of APOE, a key player in AD pathology (ref: Liu doi.org/10.1084/jem.20200474/). The protective Plcγ2-P522R variant was shown to enhance immune functions, indicating that specific genetic alterations can influence AD risk (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). Additionally, β-Hydroxybutyrate (BHB) has emerged as a promising therapeutic agent, as it inhibits NLRP3 inflammasome activation, thereby reducing plaque formation and microgliosis in the 5XFAD mouse model of AD (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). The role of Klotho in improving amyloid-β clearance and cognitive function further emphasizes the potential of targeting metabolic pathways in AD treatment (ref: Zhao doi.org/10.1111/acel.13239/). Collectively, these studies highlight the complex interplay of genetic, inflammatory, and metabolic factors in AD, paving the way for novel therapeutic strategies.

Research models of neurodegenerative diseases, particularly those focusing on microglial function, have provided significant insights into disease mechanisms. For example, the study of microglia depletion in mice infected with a neurotropic coronavirus revealed that microglia are essential for remyelination and recovery from demyelination, suggesting their critical role in neuroprotection (ref: Sariol doi.org/10.1073/pnas.2007814117/). Furthermore, the application of ultrastructural analysis in the retinogeniculate circuit demonstrated that sensory experiences can remodel neural connectivity through non-phagocytic mechanisms involving microglia (ref: Cheadle doi.org/10.1016/j.neuron.2020.08.002/). The characterization of brain-derived EVs has also shown promise in regenerative therapy, highlighting their potential role in neuroprotection following ischemic events (ref: Brenna doi.org/10.1080/20013078.2020.1809065/). These models not only enhance our understanding of the pathophysiology of neurodegenerative diseases but also facilitate the exploration of therapeutic interventions aimed at modulating microglial activity and promoting neural repair.

Microglial activation is a critical component of the immune response in the central nervous system, influencing both neuroinflammation and neurodegeneration. Studies have shown that microglial depletion can exacerbate conditions such as demyelination during viral infections, underscoring their protective role in the brain (ref: Sariol doi.org/10.1073/pnas.2007814117/). Additionally, the protective Plcγ2-P522R variant has been linked to enhanced immune functions in microglia, suggesting that genetic factors can modulate microglial responses and potentially alter disease outcomes (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). The role of interleukin-33 in mediating neuroinflammation-induced cognitive impairments further illustrates the complex interplay between microglial activation and cognitive function (ref: Reverchon doi.org/10.1186/s12974-020-01939-6/). Moreover, the impact of aging on microglial function, particularly through mechanisms involving the complement system and blood-brain barrier integrity, highlights the need for targeted therapeutic strategies to modulate microglial activity in age-related neurodegenerative diseases (ref: Propson doi.org/10.1172/JCI140966/).

Extracellular vesicles (EVs) have emerged as significant players in neuroprotection and intercellular communication within the brain. Characterization of brain-derived EVs has revealed their potential role in regenerative therapy, particularly following ischemic stroke, where they may influence neuronal survival and recovery (ref: Brenna doi.org/10.1080/20013078.2020.1809065/). Furthermore, EVs derived from human iPSC-derived neural stem cells exhibit anti-inflammatory and neurogenic properties, suggesting that they could serve as a safer alternative for brain repair compared to direct stem cell grafting (ref: Upadhya doi.org/10.1080/20013078.2020.1809064/). The interplay between microglial activation and EVs is also noteworthy, as microglia can modulate the release and uptake of EVs, thereby influencing neuroinflammatory responses and neuronal health (ref: Sariol doi.org/10.1073/pnas.2007814117/). Collectively, these findings underscore the therapeutic potential of targeting EVs in neurodegenerative diseases, providing a novel avenue for intervention.

Neuroinflammation is increasingly recognized as a key contributor to cognitive impairment in neurodegenerative diseases. Research has demonstrated that β-Hydroxybutyrate (BHB) can inhibit inflammasome activation, leading to reduced Alzheimer's disease pathology and improved cognitive outcomes in mouse models (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). Additionally, the role of interleukin-33 in mediating neuroinflammation-induced cognitive deficits highlights the complex relationship between inflammatory processes and cognitive function (ref: Reverchon doi.org/10.1186/s12974-020-01939-6/). The depletion of microglia has been shown to exacerbate demyelination and impair recovery, further linking microglial activity to cognitive health (ref: Sariol doi.org/10.1073/pnas.2007814117/). These findings suggest that targeting neuroinflammatory pathways and modulating microglial responses may offer promising strategies for mitigating cognitive decline in neurodegenerative diseases.

Therapeutic strategies targeting neurodegenerative diseases are increasingly focusing on modulating neuroinflammation and enhancing neuroprotection. The use of β-Hydroxybutyrate (BHB) has shown promise in reducing Alzheimer's disease pathology by inhibiting NLRP3 inflammasome activation, thereby mitigating cognitive decline in mouse models (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). Additionally, the characterization of extracellular vesicles (EVs) derived from human iPSC-derived neural stem cells suggests that these vesicles possess anti-inflammatory and neurogenic properties, making them a potential therapeutic tool for brain repair (ref: Upadhya doi.org/10.1080/20013078.2020.1809064/). The protective Plcγ2-P522R variant has been linked to enhanced immune functions, indicating that genetic factors may also be harnessed for therapeutic benefit (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). Furthermore, the role of Klotho in improving amyloid-β clearance and cognitive function emphasizes the potential of targeting metabolic pathways in therapeutic interventions (ref: Zhao doi.org/10.1111/acel.13239/). Collectively, these studies highlight the diverse approaches being explored to combat neurodegeneration and improve cognitive outcomes.