Microglial activation and neuroinflammation are critical components of Alzheimer's disease (AD) pathology. Recent studies have highlighted the complex inflammatory responses surrounding amyloid plaques, with Chen et al. demonstrating early transcriptional changes in a gene co-expression network enriched for oligodendrocyte genes near plaques, transitioning to a multicellular network involving inflammation and oxidative stress in later disease stages (ref: Chen doi.org/10.1016/j.cell.2020.06.038/). Nicastro et al. further explored the relationship between in vivo neuroinflammation and gray matter changes in AD patients, revealing significant alterations in brain structure associated with microglial activation (ref: Nicastro doi.org/10.1016/j.neurobiolaging.2020.06.010/). Additionally, Taylor et al. found that A1 reactive astrocytes and TREM2 loss correlate with early pathology in cerebral amyloid angiopathy, indicating a broader role of glial activation in vascular amyloid pathology (ref: Taylor doi.org/10.1186/s12974-020-01900-7/). Contradictory findings emerged from Wu et al., who reported that SRC-1 knockout did not affect amyloid beta deposition in APP/PS1 mice, suggesting that the role of specific transcription factors in AD may be more nuanced than previously thought (ref: Wu doi.org/10.3389/fnagi.2020.00145/). Overall, these studies underscore the multifaceted nature of neuroinflammation in AD, with implications for therapeutic strategies targeting microglial and astrocytic responses.

Genetic factors play a significant role in the pathogenesis of Alzheimer's disease, particularly the interactions between TREM2 and APOE genotypes. Fitz et al. demonstrated that TREM2 deficiency alters the phenotype and transcriptome of human APOE3 and APOE4 mice, suggesting that the APOE-TREM2 interaction may modulate AD pathology (ref: Fitz doi.org/10.1186/s13024-020-00394-4/). Taga et al. expanded on this by examining BIN1 protein isoforms, which are differentially expressed in astrocytes, neurons, and microglia, implicating these isoforms in tau pathology and AD susceptibility (ref: Taga doi.org/10.1186/s13024-020-00387-3/). Furthermore, Mezö et al. explored the effects of microbiota modulation on microglial responses in AD models, revealing that both germ-free and antibiotic-treated mice exhibited reduced amyloid-beta pathology and neuronal loss, indicating a potential microbiome influence on genetic risk factors (ref: Mezö doi.org/10.1186/s40478-020-00988-5/). These findings collectively highlight the intricate interplay between genetic predispositions and microglial function in AD, suggesting that targeting these interactions may offer new therapeutic avenues.

Therapeutic strategies targeting microglial function are emerging as promising avenues for Alzheimer's disease treatment. Hollinger et al. investigated the glutamine antagonist JHU-083, which normalized aberrant glutaminase activity and improved cognition in APOE4 mice, demonstrating its potential to mitigate neuroinflammation (ref: Hollinger doi.org/10.3233/JAD-190588/). Wickstead et al. proposed a novel approach by targeting the pro-resolving receptor Fpr2 to reverse microglial activation induced by inflammatory stimuli, suggesting that enhancing the resolution of inflammation could be a viable therapeutic strategy (ref: Wickstead doi.org/10.1155/2020/). Additionally, Fani Maleki et al. reported that muramyl dipeptide administration led to significant improvements in memory function and synaptic plasticity markers in AD mouse models, indicating that immunomodulation can exert beneficial effects on AD pathology (ref: Fani Maleki doi.org/10.1186/s12974-020-01893-3/). These studies emphasize the potential of targeting microglial activity and inflammatory pathways as a therapeutic strategy in AD, highlighting the need for further exploration of these approaches in clinical settings.

The gut microbiome has emerged as a significant factor influencing Alzheimer's disease pathology. Chen et al. demonstrated that alterations in gut microbiome composition precede cerebral amyloidosis and microglial pathology in a mouse model of AD, suggesting that microbiome imbalances may contribute to disease onset (ref: Chen doi.org/10.1155/2020/). Mezö et al. further explored the effects of microbiota modulation, revealing that both germ-free and antibiotic-treated mice exhibited reduced amyloid-beta burden and delayed cognitive deficits, indicating a protective role of gut microbiota against AD pathology (ref: Mezö doi.org/10.1186/s40478-020-00988-5/). These findings highlight the potential for microbiome-targeted interventions in AD prevention and treatment, suggesting that restoring a healthy gut microbiome could mitigate neuroinflammatory responses and amyloid accumulation.

Recent research has elucidated various cellular and molecular mechanisms underlying Alzheimer's disease pathology. Srinivasan et al. characterized human AD microglia, revealing enhanced aging and unique transcriptional activation profiles compared to mouse models, which may influence disease progression (ref: Srinivasan doi.org/10.1016/j.celrep.2020.107843/). Zhong et al. investigated a novel polysaccharide from Acorus tatarinowii, demonstrating its ability to inhibit TLR4-mediated neuroinflammation through the MyD88/NF-kB and PI3K/Akt signaling pathways, highlighting potential therapeutic targets for reducing neuroinflammation (ref: Zhong doi.org/10.1016/j.ijbiomac.2020.06.266/). Additionally, Goto et al. explored the neurodegeneration of trigeminal neurons and its impact on Alzheimer's pathology, suggesting that peripheral neuronal loss may exacerbate cognitive decline in AD models (ref: Goto doi.org/10.3233/JAD-200257/). These studies collectively underscore the complexity of cellular interactions and signaling pathways in AD, emphasizing the need for targeted interventions that address these mechanisms.

Understanding the dynamics of amyloid-beta and its interaction with microglia is crucial for unraveling Alzheimer's disease pathology. Henjum et al. utilized a novel mid-domain Aβ-antibody to analyze microglial uptake of amyloid-beta in transgenic mice, providing insights into the mechanisms of Aβ clearance and degradation (ref: Henjum doi.org/10.1038/s41598-020-67419-2/). Fujita et al. demonstrated that MEGF10 plays a critical role in the engulfment of toxic Aβ species by neurons and astrocytes, suggesting that enhancing this phagocytic pathway could be beneficial in AD (ref: Fujita doi.org/10.1016/j.neuroscience.2020.07.016/). Furthermore, Sanfilippo et al. found correlations between CHI3L2 expression and other inflammatory markers in AD brains, indicating that microglial responses to Aβ may be modulated by various signaling pathways (ref: Sanfilippo doi.org/10.1007/s12031-020-01667-9/). These findings highlight the importance of microglial dynamics in response to amyloid-beta and suggest potential therapeutic targets for enhancing Aβ clearance in Alzheimer's disease.