Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their interactions with apolipoprotein E (APOE) and amyloid-beta (Aβ). Kaji et al. demonstrated that APOE aggregates can initiate Aβ amyloidosis in microglia, suggesting that the endocytic uptake of APOE is a key factor in the onset of Aβ plaque formation (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). This finding aligns with the work of Tuddenham et al., who utilized single-cell RNA sequencing to profile human microglia, revealing distinct subsets associated with various functions, including antigen presentation and metabolism, which may influence their role in AD (ref: Tuddenham doi.org/10.1038/s41593-024-01764-7/). Furthermore, Gabitto et al. provided insights into the cellular populations involved in AD by employing multiomics approaches, highlighting the complexity of microglial responses in different stages of the disease (ref: Gabitto doi.org/10.1038/s41593-024-01774-5/). The immune response mediated by microglia is further complicated by genetic factors, as shown by Lu et al., who found that TRPV1 can alleviate APOE4-dependent microglial activation and T cell infiltration, indicating a potential therapeutic target for modulating neuroinflammation in AD (ref: Lu doi.org/10.1186/s40035-024-00445-6/). Zhang et al. focused on the NLRP3 inflammasome, revealing that glutamine metabolism enhances its activation in microglia, linking metabolic pathways to inflammatory responses in AD (ref: Zhang doi.org/10.1186/s12974-024-03254-w/). Additionally, Long et al. explored TREM2, a receptor that enhances microglial phagocytosis of Aβ, suggesting that targeting TREM2 signaling could modify AD progression (ref: Long doi.org/10.1186/s13195-024-01599-1/). Choi et al. emphasized the need for subtyping AD based on microglial genetic risk factors to develop more effective treatments, highlighting the heterogeneity within microglial populations (ref: Choi doi.org/10.1186/s13195-024-01583-9/).

The role of inflammation in neurodegenerative diseases is increasingly recognized, with peripheral innate immune responses contributing significantly to disease progression. Strauss et al. characterized the peripheral innate immunophenotype across various neurodegenerative conditions, identifying distinct blood-based profiles that correlate with survival outcomes (ref: Strauss doi.org/10.1038/s41380-024-02809-w/). This study underscores the importance of understanding both central and peripheral immune mechanisms in neurodegeneration. Lloyd et al. provided a comprehensive proteomic analysis of microglia, revealing significant differences between human and mouse models, particularly in inflammation-related proteins, which may affect the translational relevance of preclinical findings (ref: Lloyd doi.org/10.1016/j.celrep.2024.114908/). Machine learning approaches, as demonstrated by Miller et al., have been employed to assess behavioral changes in AD models, linking neuroinflammation to cognitive deficits and highlighting the potential for these technologies to enhance our understanding of disease mechanisms (ref: Miller doi.org/10.1016/j.celrep.2024.114870/). Furthermore, Tao et al. investigated the effects of dihydro-resveratrol on NLRP3 inflammasome activation, demonstrating its ability to mitigate neuroinflammation and cognitive decline in AD models (ref: Tao doi.org/10.1111/bph.17373/). Zhang et al. explored the modulation of microglial polarization through the Klf5/Parp14 pathway, suggesting that targeting these pathways could improve cognitive function in AD (ref: Zhang doi.org/10.1016/j.phymed.2024.156152/). Ren et al. examined the role of NLRP3 in chronic noise-induced cognitive impairment, further emphasizing the link between neuroinflammation and cognitive decline (ref: Ren doi.org/10.1016/j.ecoenv.2024.117183/). Lastly, Jiang et al. demonstrated that the SARS-CoV-2 spike protein induces neuroinflammation and cognitive impairment via the NLRP3 pathway, highlighting the broader implications of immune responses in neurodegenerative contexts (ref: Jiang doi.org/10.1016/j.expneurol.2024.115020/).

Research into the molecular mechanisms underlying Alzheimer's disease (AD) has identified several promising therapeutic targets. Kim et al. reported that a selective PPARδ agonist can reverse memory deficits in mouse models of AD, suggesting that modulation of this pathway may offer a novel therapeutic strategy (ref: Kim doi.org/10.7150/thno.96707/). Liu et al. highlighted the role of neuronal cathepsin S in promoting neuroinflammation and cognitive decline through the CX3CL1-CX3CR1 axis and JAK2-STAT3 pathway, indicating that targeting these pathways could mitigate AD pathology (ref: Liu doi.org/10.1111/acel.14393/). Zhang et al. explored the effects of intravenous chaperone treatment in late-stage AD models, finding that it impacts amyloid plaque load and reactive gliosis, thus providing evidence for the potential of chaperone-based therapies in established AD (ref: Zhang doi.org/10.1038/s41398-024-03161-x/). Tolstova et al. demonstrated that conditioned media from preconditioned mesenchymal stem cells can enhance neuroprotective effects in AD models, suggesting a role for stem cell-derived factors in neuroprotection (ref: Tolstova doi.org/10.3390/biomedicines12102243/). Lee et al. investigated the gut-brain axis, showing that DA-9601 can modulate AD pathology through the dominance of Akkermansia muciniphila, indicating that microbiome-targeted therapies may be beneficial (ref: Lee doi.org/10.1371/journal.pone.0312670/). Scarpa et al. examined the impact of chronic pain on cognitive decline, linking methylation changes in the prefrontal cortex to cognitive networks associated with AD, thus suggesting that pain management may be critical in AD prevention (ref: Scarpa doi.org/10.1016/j.neuroscience.2024.10.015/). Finally, Nakamura et al. identified a synthetic peptide that suppresses Aβ aggregation, presenting a potential therapeutic candidate for AD treatment (ref: Nakamura doi.org/10.3390/biom14101234/).

Understanding microglial heterogeneity is essential for elucidating their roles in neurodegenerative diseases. Gotkiewicz et al. provided a three-dimensional analysis of microglia-amyloid plaque interactions, revealing distinct microglial states associated with different plaque morphologies, which may influence their functional responses in AD (ref: Gotkiewicz doi.org/10.1002/glia.24628/). This study highlights the complexity of microglial behavior in the context of amyloid pathology. The impact of viral infections on microglial function was explored by Jiang et al., who demonstrated that the SARS-CoV-2 spike protein induces NLRP3-dependent neuroinflammation and cognitive impairment, suggesting that viral infections may exacerbate microglial activation in neurodegenerative contexts (ref: Jiang doi.org/10.1016/j.expneurol.2024.115020/). Additionally, Nakamura et al. focused on the aggregation of Aβ peptides, identifying a synthetic peptide that can inhibit aggregation and improve cognitive performance in AD models, emphasizing the potential for targeted therapeutic strategies (ref: Nakamura doi.org/10.3390/biom14101234/). Wang et al. conducted a bibliometric analysis of single-cell multiomics in neurodegenerative diseases, highlighting the growing interest in understanding microglial diversity and its implications for disease mechanisms (ref: Wang doi.org/10.3389/fneur.2024.1450663/).

Neuroinflammation is increasingly recognized as a key factor in cognitive decline associated with neurodegenerative diseases. Rappe et al. conducted longitudinal profiling of mitophagy in the mammalian brain, revealing that sustained mitophagy is crucial for preventing neurodegeneration, particularly in the context of aging (ref: Rappe doi.org/10.1038/s44318-024-00241-y/). This study underscores the importance of mitochondrial health in maintaining cognitive function. Ren et al. investigated the role of the NLRP3 inflammasome in chronic noise-induced cognitive impairment, finding that neuroinflammation significantly contributes to learning and memory deficits, thus linking environmental stressors to cognitive decline (ref: Ren doi.org/10.1016/j.ecoenv.2024.117183/). Wang et al. demonstrated that ouabain can ameliorate AD-associated neuropathology and cognitive impairment, suggesting that targeting neuroinflammatory pathways may provide therapeutic benefits (ref: Wang doi.org/10.3390/nu16203558/). Scarpa et al. examined the relationship between chronic pain and cognitive decline, proposing that pain-induced methylation changes in the prefrontal cortex may target cognitive networks relevant to AD (ref: Scarpa doi.org/10.1016/j.neuroscience.2024.10.015/). These findings collectively highlight the multifaceted nature of neuroinflammation and its impact on cognitive health in neurodegenerative diseases.

Identifying microglial biomarkers is crucial for advancing diagnostic approaches in neurodegenerative diseases. Duan et al. profiled extracellular vesicles from microglia and macrophages, revealing specific biomarkers such as UCHL1 and CX3CR1 that can distinguish microglial-derived vesicles in human blood, thus providing a potential avenue for non-invasive diagnostics (ref: Duan doi.org/10.1186/s12974-024-03243-z/). This study highlights the challenges in differentiating microglial responses from other immune cells in the context of neuroinflammation. Meng et al. utilized label-free chemical imaging to identify tauopathy-associated lipid signatures in AD mouse models, demonstrating that lipid metabolism plays a significant role in AD pathogenesis and could serve as a diagnostic marker (ref: Meng doi.org/10.1038/s42003-024-07034-3/). These findings emphasize the importance of integrating molecular profiling techniques to enhance our understanding of microglial function and its implications for disease diagnosis and treatment.