Microglial activation plays a crucial role in neuroinflammation, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). Zhou et al. utilized single-nucleus RNA sequencing to reveal TREM2-dependent and independent responses in microglia associated with AD pathology, highlighting the importance of TREM2 variants in increasing AD risk (ref: Zhou doi.org/10.1038/s41591-019-0695-9/). Marschallinger et al. identified a novel population of lipid-droplet-accumulating microglia (LDAM) that exhibit dysfunctional characteristics, including impaired phagocytosis and heightened proinflammatory cytokine production, which are exacerbated with aging (ref: Marschallinger doi.org/10.1038/s41593-019-0566-1/). Furthermore, El Gaamouch et al. demonstrated that the VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways, suggesting potential therapeutic avenues for reducing neuropathology in AD models (ref: El Gaamouch doi.org/10.1186/s13024-020-0357-x/). These findings collectively underscore the complex interplay between microglial activation and neuroinflammation in the aging brain and AD pathology, with TREM2 and lipid metabolism emerging as critical factors in microglial dysfunction and disease progression. In addition to AD, microglial activation has implications in other neurological conditions. Linker et al. explored the effects of adolescent nicotine exposure on microglial activation and subsequent cocaine self-administration, revealing a unique susceptibility of adolescent microglia to nicotine's effects (ref: Linker doi.org/10.1038/s41467-019-14173-3/). Wang et al. investigated the role of NF-κB c-Rel in Parkinson's disease models, finding that it has both pro-survival and anti-inflammatory roles, indicating that microglial activation can have dual effects depending on the context (ref: Wang doi.org/10.1016/j.redox.2020.101427/). Overall, these studies highlight the multifaceted roles of microglia in neuroinflammation and their potential as therapeutic targets in various neurodegenerative diseases.

Microglia are increasingly recognized for their pivotal role in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD). Zhou et al. demonstrated that TREM2 variants significantly influence microglial responses in AD, with TREM2-dependent activation linked to disease-associated microglia (DAM) (ref: Zhou doi.org/10.1038/s41591-019-0695-9/). Nugent et al. further elucidated the role of TREM2 in regulating microglial cholesterol metabolism during chronic phagocytic challenges, revealing that TREM2-deficient microglia fail to adopt a disease-associated transcriptional state, leading to neuronal damage (ref: Nugent doi.org/10.1016/j.neuron.2019.12.007/). This suggests that TREM2 is crucial for maintaining microglial functionality in the context of neurodegeneration. In addition to TREM2, other studies have explored the impact of microglial dysfunction on AD pathology. Liu et al. introduced a novel "amyloid-β cleaner" nanoparticle designed to normalize dysfunctional microglia and enhance amyloid-β recruitment, presenting a potential therapeutic strategy for AD (ref: Liu doi.org/10.1002/advs.201901555/). Meilandt et al. found that deletion of TREM2 exacerbates amyloid plaque accumulation and neuronal damage in mouse models, reinforcing the importance of microglial activity in AD progression (ref: Meilandt doi.org/10.1523/JNEUROSCI.1871-19.2019/). These findings collectively highlight the critical role of microglia in neurodegenerative diseases, emphasizing the need for further research into their mechanisms and potential therapeutic interventions.

Microglial responses to injury are complex and heterogeneous, significantly influencing outcomes in neuroinflammatory conditions. Plemel et al. utilized single-cell RNA sequencing to characterize microglial activation states following acute demyelination, revealing that distinct microglial populations can limit the dispersion of infiltrating macrophages, thereby shaping the inflammatory response (ref: Plemel doi.org/10.1126/sciadv.aay6324/). This study underscores the importance of microglial heterogeneity in orchestrating the central nervous system's response to injury and suggests that targeted modulation of specific microglial states may enhance recovery. Moreover, Yu et al. highlighted the role of dorsal root ganglion macrophages in neuropathic pain, demonstrating that these cells contribute to both the initiation and persistence of mechanical hypersensitivity following nerve injury (ref: Yu doi.org/10.1038/s41467-019-13839-2/). This finding contrasts with previous studies focusing primarily on microglial contributions, suggesting a more nuanced understanding of immune cell interactions in pain mechanisms. Additionally, Sierksma et al. reported that novel Alzheimer risk genes influence microglial responses to amyloid-β but not tau pathology, indicating that genetic factors can modulate microglial behavior in response to different types of neurodegenerative insults (ref: Sierksma doi.org/10.15252/emmm.201910606/). Collectively, these studies emphasize the critical role of microglia in injury response and repair, highlighting their potential as therapeutic targets in neuroinflammatory and neurodegenerative conditions.

The genetic and molecular underpinnings of microglial function are crucial for understanding their roles in neurodegenerative diseases. Nugent et al. explored the impact of TREM2 on microglial cholesterol metabolism, revealing that TREM2-deficient microglia exhibit a homeostatic state that fails to respond adequately to chronic phagocytic challenges, leading to neuronal damage (ref: Nugent doi.org/10.1016/j.neuron.2019.12.007/). This study highlights the importance of TREM2 in maintaining microglial functionality and its potential as a therapeutic target in Alzheimer's disease. Sierksma et al. investigated the influence of polygenic risk scores on microglial responses to amyloid-β, finding that subthreshold genetic variants can significantly affect transcriptional responses in mouse models of Alzheimer's disease (ref: Sierksma doi.org/10.15252/emmm.201910606/). This suggests that even non-significant genetic variants may contribute to disease pathology through their effects on microglial function. Additionally, Gosselin et al. emphasized the need for understanding the epigenomic and transcriptional determinants of microglial identity, as these factors are essential for their diverse roles in the central nervous system (ref: Gosselin doi.org/10.1002/glia.23787/). Together, these studies underscore the intricate genetic and molecular mechanisms that govern microglial behavior and their implications for neurodegenerative disease pathology.

The interplay between microglia and metabolic disorders has garnered increasing attention, particularly regarding their role in cognitive decline associated with obesity and diabetes. Guo et al. investigated the effects of visceral adipose NLRP3 on cognition, demonstrating that activation of the inflammasome in visceral fat can impair cognitive function via IL-1R1 signaling on microglial cells (ref: Guo doi.org/10.1172/JCI126078/). This finding highlights the potential for metabolic inflammation to influence brain health and cognitive outcomes. Ivanova et al. further explored the relationship between metabolic syndrome and cognitive impairment in a rat model, revealing that high-caloric diets exacerbate microglial activation and white matter inflammation, leading to detectable changes in spatial memory (ref: Ivanova doi.org/10.1186/s12974-020-1698-7/). This suggests that metabolic dysregulation can have profound effects on microglial function and, consequently, cognitive health. Additionally, Yamagata et al. reported that downregulation of spinal angiotensin-converting enzyme 2 is involved in neuropathic pain associated with type 2 diabetes, indicating that metabolic disorders can modulate microglial responses in pain pathways (ref: Yamagata doi.org/10.1016/j.bcp.2020.113825/). Collectively, these studies underscore the critical role of microglia in mediating the effects of metabolic disorders on brain function and highlight potential therapeutic targets for cognitive decline in metabolic disease contexts.

Microglial interactions with other cell types are essential for maintaining brain homeostasis and responding to pathological conditions. Chen et al. examined the role of the circadian regulator CLOCK in recruiting immune-suppressive microglia into the glioblastoma tumor microenvironment, suggesting that tumor-associated microglia may adopt immunosuppressive phenotypes that facilitate tumor growth (ref: Chen doi.org/10.1158/2159-8290.CD-19-0400/). This finding highlights the complex interplay between microglia and tumor cells, which may have implications for therapeutic strategies in glioblastoma. Wang et al. investigated the roles of NF-κB c-Rel in Parkinson's disease models, finding that it has both pro-survival and anti-inflammatory effects, indicating that microglial interactions with neuronal cells can significantly influence disease progression (ref: Wang doi.org/10.1016/j.redox.2020.101427/). Additionally, Jung et al. reported that the mitochondria-derived peptide Humanin can improve recovery from intracerebral hemorrhage by modulating microglial phenotype, suggesting that astrocytic interactions with microglia are critical for neurovascular unit function (ref: Jung doi.org/10.1523/JNEUROSCI.2212-19.2020/). These studies collectively emphasize the importance of microglial interactions with various cell types in both health and disease, highlighting their potential as therapeutic targets in neuroinflammatory and neurodegenerative conditions.

Therapeutic strategies targeting microglia are emerging as promising avenues for treating neurodegenerative diseases. Liu et al. introduced a zwitterionic poly(carboxybetaine)-based nanoparticle designed to normalize dysfunctional microglia and enhance amyloid-β recruitment, presenting a novel approach for Alzheimer's disease treatment (ref: Liu doi.org/10.1002/advs.201901555/). This strategy aims to restore microglial function and mitigate the pathological effects of amyloid-β accumulation. In contrast, Heras-Garvin et al. investigated the effects of a high-salt diet on neuroinflammation and neurodegeneration in a model of α-synucleinopathy, finding no significant exacerbation of neurodegenerative processes, which suggests that dietary interventions may not universally impact microglial activity (ref: Heras-Garvin doi.org/10.1186/s12974-020-1714-y/). Additionally, Yu et al. explored the neuroprotective effects of Ezetimibe in a rat model of ischemic stroke, demonstrating its ability to attenuate oxidative stress and neuroinflammation via the AMPK/Nrf2/TXNIP pathway (ref: Yu doi.org/10.1155/2020/). These findings collectively highlight the potential of various therapeutic approaches targeting microglial function to improve outcomes in neurodegenerative diseases, emphasizing the need for continued research in this area.

Microglial function is significantly influenced by developmental and aging processes, with implications for neurodegenerative disease susceptibility. Marschallinger et al. identified a population of lipid-droplet-accumulating microglia (LDAM) that emerge with aging, characterized by dysfunctional phagocytosis and increased proinflammatory cytokine production (ref: Marschallinger doi.org/10.1038/s41593-019-0566-1/). This suggests that aging may predispose microglia to a proinflammatory state that contributes to neurodegenerative processes. Chen et al. explored the role of the circadian regulator CLOCK in recruiting immune-suppressive microglia into the glioblastoma tumor microenvironment, indicating that developmental factors can influence microglial behavior in pathological contexts (ref: Chen doi.org/10.1158/2159-8290.CD-19-0400/). Furthermore, Wang et al. examined the roles of NF-κB c-Rel in Parkinson's disease models, finding that it plays a critical role in modulating microglial activation and neuroinflammation (ref: Wang doi.org/10.1016/j.redox.2020.101427/). Together, these studies underscore the importance of understanding microglial dynamics in development and aging, as they may inform therapeutic strategies for age-related neurodegenerative diseases.