Microglial activation and neuroinflammation are pivotal in the pathogenesis of Alzheimer's disease (AD). Recent studies have highlighted the role of peripheral immune cells, particularly T cells and monocytes, in exacerbating AD pathology. For instance, a three-dimensional human neuroimmune axis model demonstrated increased infiltration of T cells and monocytes in AD cultures compared to controls, suggesting that these immune cells contribute significantly to neuroinflammatory processes (ref: Jorfi doi.org/10.1038/s41593-023-01415-3/). Furthermore, tau fibrils have been shown to induce glial inflammation through the TLR2/MyD88 pathway, linking tau pathology with neuroinflammatory responses (ref: Dutta doi.org/10.1172/JCI161987/). The role of microglia in synaptic engulfment has also been elucidated, where microglia engage in synapse removal in response to neuronal hyperactivity, a hallmark of early AD (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). In addition to immune cell interactions, metabolic reprogramming of microglia has emerged as a therapeutic target. Studies have shown that oleoylethanolamide (OEA) can facilitate PPARα and TFEB signaling, attenuating Aβ pathology in mouse models (ref: Comerota doi.org/10.1186/s13024-023-00648-x/). Moreover, innovative nanomodulators targeting mTOR-mediated pathways have been developed to switch microglial polarization, demonstrating potential for managing neuroinflammation in AD (ref: Yang doi.org/10.1021/acsnano.3c03232/). Collectively, these findings underscore the complex interplay between microglial activation, immune signaling, and neuroinflammation in AD, highlighting both the pathological and potential therapeutic roles of microglia.

The molecular mechanisms underlying Alzheimer's disease (AD) are multifaceted, with neuroinflammation being a central theme. Recent research has identified SPI1/PU.1 as a transcription factor linked to AD risk, with its reduced expression correlating with delayed AD onset. Analysis of single-cell transcriptomic datasets revealed an enrichment of PU.1-binding motifs in differentially expressed genes in microglia from AD patients, suggesting a critical role in neuroinflammatory responses (ref: Ralvenius doi.org/10.1084/jem.20222105/). Additionally, the mitochondrial protein TSPO has been implicated in the severity of AD pathology, showing increased expression in the temporal cortex during later stages of the disease (ref: Garland doi.org/10.1186/s12974-023-02869-9/). The COP9 signalosome (CSN) has also been investigated for its role in neuroinflammation, with studies demonstrating that it can reduce inflammatory responses and ischemic neuronal stress in organotypic brain slice cultures (ref: Tian doi.org/10.1007/s00018-023-04911-8/). Furthermore, the immunoproteasome subunit LMP2 has been shown to play a significant role in neuroinflammatory responses, with its deficiency ameliorating LPS/Aβ-induced inflammation in AD models (ref: Guo doi.org/10.1007/s12035-023-03564-9/). These findings highlight the intricate molecular pathways involved in AD, emphasizing the potential for targeting these mechanisms to mitigate neuroinflammation and its associated cognitive decline.

Therapeutic strategies targeting microglia and neuroinflammation are gaining traction in the fight against Alzheimer's disease (AD). Oleoylethanolamide (OEA) has been identified as a promising agent that facilitates PPARα and TFEB signaling, leading to a reduction in Aβ pathology in mouse models (ref: Comerota doi.org/10.1186/s13024-023-00648-x/). Additionally, the immunoproteasome subunit LMP2 has been shown to play a crucial role in neuroinflammatory responses, with its deficiency providing neuroprotective effects against LPS/Aβ-induced inflammation (ref: Guo doi.org/10.1007/s12035-023-03564-9/). Moreover, the antioxidant astaxanthin has demonstrated the ability to enhance autophagy and promote Aβ clearance while exerting anti-inflammatory effects in in vitro models of AD (ref: Babalola doi.org/10.1016/j.brainres.2023.148518/). This suggests that dietary interventions may also play a role in modulating neuroinflammation and improving cognitive outcomes. Furthermore, the R47H variant of TREM2, which increases AD risk, has been linked to aberrant synapse density and network hyperexcitability, indicating that genetic factors may influence therapeutic responses (ref: Das doi.org/10.1016/j.nbd.2023.106263/). Collectively, these studies underscore the potential of targeting microglial function and neuroinflammatory pathways as a therapeutic avenue in AD management.

Extracellular vesicles (EVs) have emerged as significant players in Alzheimer's disease (AD), serving as both biomarkers and potential therapeutic targets. A comprehensive characterization of human brain-derived EVs revealed differences in yield, morphology, and protein cargo depending on the isolation method used, emphasizing the need for standardized protocols in EV research (ref: Zhang doi.org/10.1002/jev2.12358/). These findings suggest that EVs could provide valuable insights into the physiological changes occurring in the AD brain and may facilitate the development of diagnostic tools. In addition to EVs, the role of amyloid-beta (Aβ) in neuroinflammation has been extensively studied. The antioxidant astaxanthin has been shown to enhance Aβ clearance and exert anti-inflammatory effects in models of AD-related blood-brain barrier dysfunction (ref: Babalola doi.org/10.1016/j.brainres.2023.148518/). Furthermore, the immunoproteasome subunit LMP2 has been implicated in the inflammatory response to Aβ, with its deficiency ameliorating neuroinflammatory processes in AD models (ref: Guo doi.org/10.1007/s12035-023-03564-9/). These studies highlight the intricate relationship between EVs, Aβ, and neuroinflammation, suggesting that targeting these pathways could offer new therapeutic strategies for AD.

Sex differences in microglial function and their implications for Alzheimer's disease (AD) are becoming increasingly recognized. Research has shown that microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus, which may explain the higher prevalence of AD in females (ref: Ocañas doi.org/10.1186/s12974-023-02870-2/). This study highlights the need for further investigation into how sex-specific factors influence microglial behavior and neuroinflammatory responses in the context of aging and AD. Additionally, dietary factors have been shown to impact microglial morphology and function. A study demonstrated that dietary fiber intake affects microglial clustering and cognitive functions in both wild-type and 5xFAD mice, suggesting that maternal dietary habits may influence offspring's cognitive outcomes and microglial transcriptome (ref: Zhou doi.org/10.1523/JNEUROSCI.0724-23.2023/). These findings underscore the importance of considering sex and age as critical variables in AD research, as they may significantly influence microglial activity and the progression of neurodegenerative processes.

Dietary and lifestyle factors play a crucial role in the development and progression of Alzheimer's disease (AD). Recent studies have highlighted the impact of dietary fiber and microbiota metabolite receptors on cognitive function and disease alleviation in mouse models of AD. Specifically, the depletion of GPR41 and GPR43 receptors accelerated cognitive decline and impaired neurogenesis, indicating that dietary interventions may have significant implications for AD management (ref: Zhou doi.org/10.1523/JNEUROSCI.0724-23.2023/). Moreover, the antioxidant astaxanthin has been shown to enhance autophagy and promote Aβ clearance while exerting anti-inflammatory effects in in vitro models of AD (ref: Babalola doi.org/10.1016/j.brainres.2023.148518/). This suggests that dietary antioxidants may serve as potential therapeutic agents in combating neuroinflammation and cognitive decline associated with AD. Collectively, these findings emphasize the importance of dietary and lifestyle factors in modulating neuroinflammation and cognitive outcomes in AD, highlighting the potential for preventive strategies through nutritional interventions.

Genetic and environmental factors significantly influence microglial activity and their role in Alzheimer's disease (AD). Recent studies have identified IGFBPL1 as a key regulator of microglial homeostasis and the resolution of neuroinflammation, suggesting that genetic variations may dictate microglial responses to injury and inflammation (ref: Pan doi.org/10.1016/j.celrep.2023.112889/). This highlights the potential for genetic factors to modulate the inflammatory phenotype of microglia, which is crucial in the context of neurodegenerative diseases. Furthermore, the role of astrocytes in neuroinflammation has been emphasized, with therapies targeting reactive astrocytes showing promise in rescuing cognitive impairment caused by neuroinflammation (ref: Nakano-Kobayashi doi.org/10.1073/pnas.2303809120/). This suggests that environmental factors, such as inflammatory cytokines released from microglia, can influence astrocyte behavior and contribute to neuronal loss. Together, these findings underscore the complex interplay between genetic predispositions and environmental influences in shaping microglial activity and their contributions to AD pathology.

Innovative models and techniques are essential for advancing our understanding of Alzheimer's disease (AD) and its underlying mechanisms. Recent studies have utilized systems genetics methods to identify IGFBPL1 as a master regulator of microglial homeostasis and the resolution of neuroinflammation, providing insights into the molecular signals that govern microglial behavior (ref: Pan doi.org/10.1016/j.celrep.2023.112889/). This approach highlights the potential for genetic models to elucidate the pathways involved in neuroinflammatory responses in AD. Additionally, the use of immunoproteasome subunit LMP2 deficiency has been explored as a therapeutic strategy, demonstrating its role in ameliorating LPS/Aβ-induced inflammation in AD models (ref: Guo doi.org/10.1007/s12035-023-03564-9/). Furthermore, the antioxidant astaxanthin has shown promise in enhancing Aβ clearance and exerting anti-inflammatory effects in in vitro models of AD (ref: Babalola doi.org/10.1016/j.brainres.2023.148518/). These innovative approaches underscore the importance of developing new models and techniques to better understand the complex interactions between genetic factors, microglial activity, and neuroinflammation in AD.