Research into microglial activation has revealed its critical role in various neurodegenerative diseases, particularly Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). A study demonstrated that C9orf72 deficiency leads to microglial activation characterized by an inflammatory state and an enhanced type I interferon signature, which may contribute to synaptic loss and amyloid accumulation (ref: Lall doi.org/10.1016/j.neuron.2021.05.020/). In contrast, another study found that activated microglia can mitigate Aβ-associated tau seeding and spreading, suggesting a protective role under certain conditions (ref: Gratuze doi.org/10.1084/jem.20210542/). This duality in microglial function highlights the complexity of their role in neurodegeneration, where they can both exacerbate and alleviate pathology depending on the context. Furthermore, the study of visceral adipose tissue revealed that systemic inflammation can lead to macrophage influx into the hypothalamus, indicating that peripheral inflammation may influence central nervous system (CNS) pathology (ref: Chen doi.org/10.1186/s12974-021-02183-2/). Hyperactivation of monocytes and macrophages in mild cognitive impairment (MCI) patients has also been linked to the progression of AD, underscoring the importance of understanding both central and peripheral immune responses in neurodegenerative diseases (ref: Munawara doi.org/10.1186/s12979-021-00236-x/). Overall, these findings emphasize the intricate interplay between microglial activation, systemic inflammation, and neurodegenerative processes.

The immune response in the central nervous system (CNS) is crucial for managing infections and maintaining homeostasis. A study highlighted the role of MyD88 signaling in neurons, which induces chemokines that recruit protective leukocytes to the CNS during viral infections, such as those caused by vesicular stomatitis virus (VSV) (ref: Ghita doi.org/10.1126/sciimmunol.abc9165/). This recruitment is essential for controlling inflammation and preventing neuronal damage. Additionally, the study of chronic traumatic encephalopathy (CTE) revealed that repetitive head injuries lead to unique immunological changes, including the enrichment of immunoglobulins and extracellular matrix proteins, which correlate with disease progression (ref: Gutierrez-Quiceno doi.org/10.1186/s13024-021-00462-3/). Furthermore, the protective effects of annexin A1 were demonstrated, as it restored blood-brain barrier integrity and reduced amyloid-β and tau pathology in mouse models, suggesting potential therapeutic avenues for neuroinflammatory conditions (ref: Ries doi.org/10.1093/brain/). The interplay between systemic inflammation and CNS responses is further illustrated by the influx of macrophages from visceral adipose tissue into the hypothalamus, which contributes to neuroinflammation (ref: Chen doi.org/10.1186/s12974-021-02183-2/). These studies collectively underscore the importance of understanding the immune mechanisms in the CNS and their implications for neurodegenerative diseases.

Microglia play a pivotal role in the pathology of Alzheimer's disease (AD), with recent studies elucidating their complex functions. One study found that activated microglia can mitigate Aβ-associated tau seeding and spreading, suggesting a protective role in the context of amyloid pathology (ref: Gratuze doi.org/10.1084/jem.20210542/). Conversely, another investigation revealed that replicative senescence in microglia contributes to the emergence of disease-associated microglia (DAM) and correlates with Aβ pathology, indicating that prolonged microglial activation may exacerbate disease progression (ref: Hu doi.org/10.1016/j.celrep.2021.109228/). Additionally, the stimulation of innate immunity via CpG oligodeoxynucleotides was shown to ameliorate AD pathology in aged squirrel monkeys, highlighting the potential for immune modulation as a therapeutic strategy (ref: Patel doi.org/10.1093/brain/). The use of focused ultrasound combined with anti-Aβ antibodies also demonstrated enhanced efficacy in reducing plaque burden and improving synaptic health in AD-like mice, further emphasizing the role of microglia in responding to therapeutic interventions (ref: Sun doi.org/10.1016/j.jconrel.2021.06.037/). These findings collectively illustrate the dual nature of microglial responses in AD, where they can both contribute to and mitigate disease pathology.

Microglial function extends beyond immune responses, influencing behavioral adaptations and neurodevelopment. A study investigating the effects of chronic restraint stress (CRS) on microglia found that these cells contribute to social behavioral adaptation, with wild-type mice exhibiting enhanced social dominance and spatial learning despite stress exposure (ref: Piirainen doi.org/10.1002/glia.24053/). This suggests that microglia may play a role in promoting resilience to stress. In contrast, research on X-linked adrenoleukodystrophy (CALD) highlighted the detrimental effects of concurrent axon and myelin destruction, differentiating it from multiple sclerosis (ref: Bergner doi.org/10.1002/glia.24042/). Furthermore, the upregulation of ganglioside GD3 in microglia following global cerebral ischemia was shown to regulate phagocytosis, indicating that microglial metabolism and surface markers can influence their functional capacity (ref: Wang doi.org/10.1111/jnc.15455/). The association of G protein-coupled receptor kinases with AD pathology further underscores the multifaceted roles of microglia in both health and disease (ref: Guimarães doi.org/10.1111/nan.12742/). Together, these studies highlight the diverse functions of microglia in modulating behavior and responding to neurological insults.

Neuroinflammation is a critical factor in the progression of various neurological disorders, and recent studies have explored its implications for neuroprotection. MyD88 signaling in neurons has been shown to induce the recruitment of protective leukocytes to the CNS during viral infections, which is essential for mitigating damage (ref: Ghita doi.org/10.1126/sciimmunol.abc9165/). Additionally, the proteomic analysis of chronic traumatic encephalopathy (CTE) revealed stage-specific molecular phenotypes associated with neuroinflammation, highlighting the role of immunoglobulins and extracellular matrix proteins in disease progression (ref: Gutierrez-Quiceno doi.org/10.1186/s13024-021-00462-3/). The protective effects of annexin A1 were also demonstrated, as it restored blood-brain barrier integrity and reduced amyloid-β and tau pathology in mouse models, suggesting potential therapeutic strategies for neuroinflammatory conditions (ref: Ries doi.org/10.1093/brain/). Furthermore, the hyperactivation of monocytes and macrophages in MCI patients has been linked to the progression of Alzheimer's disease, indicating that peripheral immune responses can significantly impact CNS pathology (ref: Munawara doi.org/10.1186/s12979-021-00236-x/). Collectively, these findings underscore the importance of understanding neuroinflammation and its potential for therapeutic intervention in neurodegenerative diseases.

Microglial metabolism is increasingly recognized as a pivotal factor influencing the risk and progression of Alzheimer's disease (AD), particularly in relation to sex differences. A study found that female microglia in APP/PS1 mice exhibited a glycolytic metabolism and reduced phagocytic activity, correlating with increased amyloidosis, while male microglia displayed a more amoeboid morphology associated with lower plaque loads (ref: Guillot-Sestier doi.org/10.1038/s42003-021-02259-y/). This suggests that metabolic differences in microglia may contribute to the observed sex disparities in AD prevalence. Additionally, the therapeutic potential of three-dimensional cultured mesenchymal stem cells (MSCs) was explored, demonstrating enhanced repair of ischemic stroke through inhibition of microglial activation, indicating that modulating microglial metabolism could have beneficial effects in neurodegenerative contexts (ref: Li doi.org/10.1186/s13287-021-02416-4/). The hyperactivation of monocytes and macrophages in MCI patients further emphasizes the role of systemic inflammation in the aging brain and its contribution to AD progression (ref: Munawara doi.org/10.1186/s12979-021-00236-x/). These findings highlight the intricate relationship between microglial metabolism, aging, and neurodegenerative disease pathology.

The response of microglia to injury is a critical area of research, particularly in understanding their role in neurodegenerative diseases. A study demonstrated that replicative senescence in microglia contributes to the emergence of disease-associated microglia (DAM) and correlates with Aβ pathology, suggesting that prolonged microglial activation may exacerbate Alzheimer's disease progression (ref: Hu doi.org/10.1016/j.celrep.2021.109228/). Additionally, research on atypical perineuronal nets in the CA2 region of the hippocampus revealed their interference with social memory in a mouse model of social dysfunction, highlighting the importance of microglial interactions with neuronal structures in response to injury (ref: Cope doi.org/10.1038/s41380-021-01174-2/). The study of X-linked adrenoleukodystrophy (CALD) further illustrated the relationship between axonal damage and myelin loss, emphasizing the need for targeted interventions to mitigate microglial activation in such conditions (ref: Bergner doi.org/10.1002/glia.24042/). Furthermore, brain iron enrichment was shown to attenuate α-synuclein spreading after injection of preformed fibrils, indicating that microglial responses can be influenced by environmental factors (ref: Dauer Née Joppe doi.org/10.1111/jnc.15461/). Together, these studies underscore the complex and multifaceted nature of microglial responses to injury and their implications for neurodegenerative disease pathology.