Research on microglial function in Alzheimer's disease (AD) has revealed critical insights into the role of genetic variants and inflammatory responses. A study established isogenic human embryonic stem cell-derived microglia-like cell lines harboring AD variants, demonstrating that AD-like expression signatures were particularly evident in SORL1 and TREM2 variants, with APOE identified as a key pathogenic node (ref: Liu doi.org/10.1084/jem.20200474/). Another investigation focused on the PLCG2 gene variant, Plcγ2-P522R, which was shown to enhance immune functions and reduce AD risk in a knock-in mouse model, highlighting the importance of microglial genetic variants in AD pathology (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). Additionally, the interplay between amyloid pathology and hyperhomocysteinemia was explored, revealing that dietary-induced hyperhomocysteinemia exacerbates amyloid deposition and inflammatory responses in aged mouse models (ref: Braun doi.org/10.1186/s12974-020-01938-7/). Further studies have demonstrated that β-hydroxybutyrate can inhibit NLRP3 inflammasome activation, thereby reducing AD pathology in the 5XFAD mouse model, which underscores the potential for metabolic interventions in AD treatment (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). The beneficial effects of Klotho overexpression on amyloid-β clearance and cognitive function were also noted, indicating that enhancing this pathway could ameliorate AD-related cognitive deficits (ref: Zhao doi.org/10.1111/acel.13239/). Moreover, TREM2's role in promoting anti-inflammatory responses in microglia was confirmed, with reduced TREM2 expression leading to diminished anti-inflammatory gene responses (ref: Liu doi.org/10.1093/hmg/). Lastly, the ability of liquiritigenin to shift microglial polarization from M1 to M2 type, thereby decreasing Aβ levels and cognitive decline, suggests a therapeutic avenue for AD (ref: Du doi.org/10.1007/s12640-020-00284-z/).

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease, with various studies elucidating the mechanisms underlying immune responses in the brain. One study highlighted the protective function of astrocytes in maintaining β-amyloid homeostasis, identifying Peroxiredoxin 6 as a crucial factor in astrocytic responses to Aβ plaques (ref: Pankiewicz doi.org/10.1186/s13024-020-00401-8/). Another investigation revealed that aging is associated with increased vascular inflammation and blood-brain barrier permeability, mediated by the endothelial C3a receptor, which underscores the interconnectedness of vascular and immune dysfunction in neurodegeneration (ref: Propson doi.org/10.1172/JCI140966/). Additionally, the development of a high-performance secretome analysis method allowed for the identification of cell type-resolved secretory responses during neuroinflammation, providing insights into the molecular communication within the brain (ref: Tüshaus doi.org/10.15252/embj.2020105693/). The lipid composition of the brain was also characterized through quantitative shotgun lipidomics, revealing important insights into the role of lipids in brain function and their potential implications in neuroinflammatory processes (ref: Fitzner doi.org/10.1016/j.celrep.2020.108132/). Furthermore, the role of TREM2 in modulating microglial responses to inflammation was reaffirmed, with reduced TREM2 expression leading to impaired anti-inflammatory signaling (ref: Liu doi.org/10.1093/hmg/). Systemic exposure to lipopolysaccharides was shown to induce AD-like pathologies, correlating inflammatory markers with cognitive decline, thereby linking peripheral inflammation to neurodegeneration (ref: Gu doi.org/10.3233/JAD-200689/).

The exploration of pathological mechanisms in Alzheimer's disease has identified various environmental and biological factors contributing to disease progression. One study demonstrated that exposure to benzo(a)pyrene led to neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice, emphasizing the impact of environmental toxins on AD pathology (ref: Liu doi.org/10.1186/s12974-020-01925-y/). Another significant finding was the role of β-hydroxybutyrate in inhibiting NLRP3 inflammasome activation, which resulted in reduced AD pathology in a transgenic mouse model, suggesting that metabolic modulation could be a viable therapeutic strategy (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). The study of Klotho overexpression revealed its potential to improve amyloid-β clearance and cognitive function, indicating that enhancing this pathway may mitigate AD-related deficits (ref: Zhao doi.org/10.1111/acel.13239/). Additionally, systemic exposure to lipopolysaccharides from Porphyromonas gingivalis was shown to induce bone loss and correlate with AD-like pathologies, linking oral health to neurodegenerative processes (ref: Gu doi.org/10.3233/JAD-200689/). Traumatic injury was also found to reduce amyloid plaque burden in the spinal cord of 5xFAD mice, suggesting that physical trauma may influence amyloid pathology and microglial activity (ref: Chu doi.org/10.3233/JAD-200387/). Lastly, the characterization of the brain lipidome provided insights into the lipid composition changes associated with neurodegeneration, which may inform future therapeutic approaches (ref: Fitzner doi.org/10.1016/j.celrep.2020.108132/).

Recent advancements in therapeutic approaches for Alzheimer's disease have focused on targeting specific molecular pathways and enhancing neuroprotective mechanisms. The inhibition of the NLRP3 inflammasome by β-hydroxybutyrate was shown to significantly reduce AD pathology in the 5XFAD mouse model, suggesting that metabolic interventions could be beneficial in managing neuroinflammation and amyloid deposition (ref: Shippy doi.org/10.1186/s12974-020-01948-5/). Klotho overexpression was also found to improve amyloid-β clearance and cognitive function in APP/PS1 mice, indicating that enhancing this pathway could serve as a promising therapeutic strategy (ref: Zhao doi.org/10.1111/acel.13239/). Moreover, the role of TREM2 in promoting anti-inflammatory responses in microglia was investigated, revealing that reduced TREM2 expression leads to diminished anti-inflammatory signaling, which could inform future drug development aimed at modulating microglial activity (ref: Liu doi.org/10.1093/hmg/). Liquiritigenin was identified as a compound that decreases Aβ levels and ameliorates cognitive decline by regulating microglial M1/M2 transformation, highlighting its potential as a therapeutic agent (ref: Du doi.org/10.1007/s12640-020-00284-z/). Additionally, the measurement of intracellular nitric oxide production in microglia using microfluidic single-cell analysis presents a novel approach to target neuroinflammation in neurodegenerative diseases (ref: Sibbitts doi.org/10.1039/d0ay01578d/). The exploration of osthole's effects on Aβ deposition through NLRP3 inflammasome inhibition further emphasizes the importance of targeting inflammatory pathways in drug development (ref: Liu doi.org/10.1248/bpb.b20-00112/).

Genetic and molecular studies have provided significant insights into the mechanisms underlying Alzheimer's disease, particularly focusing on microglial function and genetic variants. The identification of the PLCG2 gene variant Plcγ2-P522R, which promotes immune functions and reduces AD risk, underscores the importance of microglial-specific genetic variants in disease etiology (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). Additionally, research on hyperhomocysteinemia as a risk factor for AD revealed that it enhances amyloid deposition and inflammatory responses, highlighting the interplay between genetic predispositions and environmental factors (ref: Braun doi.org/10.1186/s12974-020-01938-7/). The role of TREM2 in modulating microglial responses was further elucidated, showing that reduced TREM2 expression leads to impaired anti-inflammatory signaling, which may contribute to AD pathology (ref: Liu doi.org/10.1093/hmg/). The systemic exposure to lipopolysaccharides from Porphyromonas gingivalis was linked to AD-like pathologies, indicating that peripheral inflammation can influence neurodegenerative processes (ref: Gu doi.org/10.3233/JAD-200689/). Furthermore, cerebrospinal fluid levels of soluble TREM2 were found to correlate with clinical presentations of AD, suggesting its potential as a biomarker for disease progression (ref: Knapskog doi.org/10.1038/s41598-020-72878-8/). These findings collectively emphasize the critical role of genetic and molecular factors in understanding and potentially targeting Alzheimer's disease.

The interactions between various cell types in the brain are crucial for understanding the mechanisms of neurodegeneration in Alzheimer's disease. A multi-omic study of human embryonic stem cell-derived microglia-like cells revealed that variants in genes associated with AD, such as CD33, INPP5D, SORL1, and TREM2, converge at the APOE locus, suggesting a shared pathway in disease pathology (ref: Liu doi.org/10.1084/jem.20200474/). This highlights the importance of microglial function in the context of genetic risk factors for AD. Additionally, the PLCG2 variant was shown to enhance immune functions in microglia, further emphasizing the role of genetic variants in modulating cellular interactions and responses in neurodegeneration (ref: Takalo doi.org/10.1186/s13024-020-00402-7/). The study of hyperhomocysteinemia demonstrated its impact on amyloid pathology, indicating that dietary factors can influence microglial responses and amyloid deposition (ref: Braun doi.org/10.1186/s12974-020-01938-7/). Furthermore, traumatic injury was found to reduce amyloid plaque burden in the spinal cord of 5xFAD mice, suggesting that physical trauma can alter microglial activity and amyloid dynamics (ref: Chu doi.org/10.3233/JAD-200387/). The systemic exposure to lipopolysaccharides was linked to increased inflammatory markers and cognitive decline, illustrating how peripheral factors can affect neuroinflammatory processes in the brain (ref: Gu doi.org/10.3233/JAD-200689/). These studies collectively underscore the complexity of cellular interactions in the pathogenesis of Alzheimer's disease and the need for a multifaceted approach to therapeutic development.

Environmental and lifestyle factors have been increasingly recognized as significant contributors to the risk and progression of Alzheimer's disease. A study demonstrated that exposure to benzo(a)pyrene resulted in neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice, highlighting the detrimental effects of environmental toxins on brain health (ref: Liu doi.org/10.1186/s12974-020-01925-y/). This finding emphasizes the need to consider environmental exposures when assessing AD risk. Additionally, Klotho overexpression was shown to improve amyloid-β clearance and cognitive function, suggesting that lifestyle factors that enhance Klotho levels could have protective effects against AD (ref: Zhao doi.org/10.1111/acel.13239/). Traumatic injury was also found to reduce amyloid plaque burden in transgenic mice, indicating that physical trauma may influence amyloid pathology and microglial activity (ref: Chu doi.org/10.3233/JAD-200387/). Furthermore, the measurement of intracellular nitric oxide production in microglia using microfluidic single-cell analysis presents a novel approach to understanding how lifestyle factors may modulate neuroinflammation and neurodegeneration (ref: Sibbitts doi.org/10.1039/d0ay01578d/). These findings collectively underscore the importance of considering environmental and lifestyle factors in the context of Alzheimer's disease, as they may offer new avenues for prevention and intervention.