Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in their interaction with amyloid-beta (Aβ) plaques. Huang et al. demonstrated that microglial TAM receptors Axl and Mer are essential for the detection and clearance of Aβ plaques in mouse models of AD. Genetic ablation of these receptors resulted in impaired microglial function, leading to reduced phagocytosis of Aβ plaques (ref: Huang doi.org/10.1038/s41590-021-00913-5/). Additionally, March-Diaz et al. explored how hypoxia affects microglial metabolism in AD, revealing that activation of the hypoxia-inducible factor 1 (HIF1) pathway compromises mitochondrial function and promotes microglial quiescence, which may contribute to AD progression (ref: March-Diaz doi.org/10.1038/s43587-021-00054-2/). Ozawa et al. introduced a novel approach using photo-oxygenation to enhance microglial clearance of aggregated Aβ, showing significant reductions in plaque levels in AD model mice (ref: Ozawa doi.org/10.1093/brain/). These findings highlight the multifaceted roles of microglia in AD, from plaque clearance to metabolic adaptations under stress conditions. The interplay between microglia and other glial cells, such as astrocytes, is also critical in AD. Park et al. found that blocking microglial activation of reactive astrocytes provides neuroprotection in AD models, suggesting that neuroinflammation mediated by microglia exacerbates disease severity (ref: Park doi.org/10.1186/s40478-021-01180-z/). Furthermore, the expression of TREM2, a receptor linked to AD risk, is modulated by MEK1/2 activity, as shown by Schapansky et al., indicating that signaling pathways influencing microglial function could be potential therapeutic targets (ref: Schapansky doi.org/10.1074/jbc.RA120.014352/). The review by Chen et al. emphasizes the impact of genetic factors like APOE genotype, sex, and aging on microglial function in AD, revealing that female microglia may lose their protective effects in the context of AD (ref: Chen doi.org/10.3389/fnagi.2021.631827/). Overall, these studies underscore the complex role of microglia in AD, highlighting both their protective and detrimental functions.

Neuroinflammation is a central feature of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease. Trudler et al. demonstrated that soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in human induced pluripotent stem cell-derived microglia, suggesting a mechanism by which neuroinflammation may contribute to neuronal death in Parkinson's disease (ref: Trudler doi.org/10.1073/pnas.2025847118/). In the context of AD, Kim et al. found that therapeutic B-cell depletion can reverse disease progression, highlighting the role of activated B cells in the pathophysiology of AD (ref: Kim doi.org/10.1038/s41467-021-22479-4/). This study indicates that B cells may contribute to neuroinflammation beyond their role in antibody production, suggesting a more complex immune interaction in AD. Further investigations into neuroinflammation revealed that dietary factors can influence disease pathology. Wińckowska-Gacek et al. reported that a Western diet exacerbates neuroinflammation and amyloid pathology in AD, indicating that lifestyle choices may modulate disease risk (ref: Wińckowska-Gacek doi.org/10.3389/fnagi.2021.654509/). Udomruk et al. explored the effects of sesamin on microglial reactivity induced by advanced glycation end products, demonstrating its potential to suppress neuroinflammation through inhibition of key signaling pathways (ref: Udomruk doi.org/10.1016/j.brainresbull.2021.04.012/). Additionally, Kim et al. introduced a novel nutritional mixture that prevents memory impairment by inhibiting NLRP3 inflammasome formation in transgenic mice, further supporting the idea that dietary interventions can mitigate neuroinflammation (ref: Kim doi.org/10.1080/1028415X.2021.1913952/). Collectively, these studies highlight the intricate relationship between neuroinflammation and immune responses in neurodegenerative diseases, emphasizing the potential for therapeutic strategies targeting these pathways.

Amyloid-beta (Aβ) pathology is a hallmark of Alzheimer's disease (AD), and understanding its clearance mechanisms is crucial for developing effective therapies. Ozawa et al. demonstrated that photo-oxygenation enhances microglial degradation of aggregated Aβ in AD model mice, providing a promising approach to facilitate plaque clearance (ref: Ozawa doi.org/10.1093/brain/). Huang et al. further elucidated the role of microglial TAM receptors Axl and Mer in detecting and engulfing Aβ plaques, showing that their genetic ablation impairs microglial function and plaque clearance (ref: Huang doi.org/10.1038/s41590-021-00913-5/). These findings underscore the importance of microglial activity in managing Aβ levels in the brain. In addition to microglial mechanisms, Dyne et al. explored the use of mild magnetic nanoparticle hyperthermia to promote the disaggregation of Aβ plaques, demonstrating its potential to enhance microglial-mediated clearance (ref: Dyne doi.org/10.1016/j.nano.2021.102397/). This innovative approach highlights the need for novel strategies to target Aβ accumulation. Vasilopoulou et al. investigated the effects of chronic low-dose treatment with LSL60101 in 5XFAD mice, revealing improvements in cognitive deficits and reductions in Aβ burden, suggesting that pharmacological interventions can modify amyloid pathology (ref: Vasilopoulou doi.org/10.1111/bph.15478/). These studies collectively emphasize the critical role of both microglial function and novel therapeutic strategies in addressing amyloid pathology in AD.

Genetic and environmental factors significantly influence the risk and progression of Alzheimer's disease (AD). Wickstead et al. highlighted the role of neuroinflammation in AD, emphasizing that strategies to modulate microglial activity could provide new avenues for treatment (ref: Wickstead doi.org/10.1111/febs.15861/). The study underscores the importance of understanding genetic predispositions, such as rare variants in the TREM2 gene, which have been linked to increased AD risk. Schapansky et al. investigated the modulation of TREM2 surface expression by MEK1/2 signaling, revealing potential therapeutic targets for enhancing microglial function in AD (ref: Schapansky doi.org/10.1074/jbc.RA120.014352/). Environmental factors, particularly diet, also play a crucial role in AD pathology. Wińckowska-Gacek et al. demonstrated that a Western diet exacerbates neuroinflammation and amyloid pathology, suggesting that dietary choices can influence disease progression (ref: Wińckowska-Gacek doi.org/10.3389/fnagi.2021.654509/). Udomruk et al. explored the impact of advanced glycation end products on microglial reactivity, indicating that dietary components can modulate inflammatory responses in the brain (ref: Udomruk doi.org/10.1016/j.brainresbull.2021.04.012/). Furthermore, Qiu et al. reported significant transcriptional changes in microglia related to metabolism in an AD mouse model, suggesting that genetic and environmental factors may interact to influence microglial function and, consequently, AD pathology (ref: Qiu doi.org/10.3233/JAD-210213/). Together, these studies highlight the complex interplay between genetic predispositions and environmental influences in the context of AD.

The development of effective therapeutic strategies for Alzheimer's disease (AD) remains a significant challenge due to its multifactorial nature. Rossi et al. introduced the concept of multi-target-directed ligands (MTDLs) derived from cashew nutshell liquid, showcasing their potential as sustainable drug candidates with anti-inflammatory properties (ref: Rossi doi.org/10.1021/acs.jmedchem.1c00048/). This innovative approach emphasizes the need for accessible and effective treatments, particularly in developing countries. Additionally, Hao et al. investigated the effects of bulbocodin D on cognitive impairment in APP/PS1 transgenic mice, demonstrating its ability to modulate amyloid-beta burden and neuroinflammation (ref: Hao doi.org/10.1007/s00213-021-05832-9/). These findings provide preclinical evidence for the therapeutic potential of bulbocodin D in AD. Furthermore, Kim et al. explored a novel nutritional mixture that prevents memory impairment by inhibiting NLRP3 inflammasome formation in 5xFAD transgenic mice, highlighting the role of dietary interventions in AD management (ref: Kim doi.org/10.1080/1028415X.2021.1913952/). Udomruk et al. also reported that sesamin suppresses microglial reactivity induced by advanced glycation end products, suggesting that targeting neuroinflammation could be a viable therapeutic strategy (ref: Udomruk doi.org/10.1016/j.brainresbull.2021.04.012/). Collectively, these studies underscore the importance of exploring diverse therapeutic approaches, including pharmacological, nutritional, and lifestyle interventions, to address the complex pathology of AD.

Microglial heterogeneity is increasingly recognized as a critical factor in the progression of Alzheimer's disease (AD). Sorrentino et al. emphasized that microglia may contribute to the phenotypic diversity observed in AD by releasing distinct cytokines that can either promote or inhibit neuroinflammation (ref: Sorrentino doi.org/10.3390/ijms22052780/). This variability in microglial response may influence disease outcomes and highlights the need for a deeper understanding of microglial function in different AD contexts. Chen et al. reviewed the interplay between microglia and key risk factors for AD, such as APOE genotype, sex, and aging, noting that female microglia may lose their protective effects in the context of AD, potentially accelerating disease progression (ref: Chen doi.org/10.3389/fnagi.2021.631827/). Additionally, Qiu et al. reported significant transcriptional changes in microglia related to metabolism in an AD mouse model, indicating that microglial function evolves throughout the disease process (ref: Qiu doi.org/10.3233/JAD-210213/). Liu et al. investigated the cerebrovascular changes associated with diabetes and their implications for AD susceptibility, suggesting that aging and metabolic disorders may further complicate microglial responses (ref: Liu doi.org/10.1177/0271678X211006596/). These studies collectively highlight the importance of considering microglial heterogeneity and aging in the context of AD, as they may significantly influence disease pathology and therapeutic outcomes.

Neurodegeneration and cognitive impairment are central features of Alzheimer's disease (AD), and understanding their underlying mechanisms is crucial for developing effective interventions. Vasilopoulou et al. demonstrated that chronic low-dose treatment with LSL60101 in 5XFAD mice reversed cognitive deficits and improved social behavior, indicating its potential as a disease-modifying therapy (ref: Vasilopoulou doi.org/10.1111/bph.15478/). This study highlights the importance of targeting cognitive function in AD treatment strategies. Additionally, Kim et al. introduced a novel nutritional mixture that prevents memory impairment by inhibiting NLRP3 inflammasome formation, suggesting that dietary interventions may mitigate cognitive decline in AD (ref: Kim doi.org/10.1080/1028415X.2021.1913952/). Furthermore, Udomruk et al. explored the effects of sesamin on microglial reactivity induced by advanced glycation end products, revealing its anti-inflammatory properties that may contribute to cognitive protection (ref: Udomruk doi.org/10.1016/j.brainresbull.2021.04.012/). Daini et al. conducted a regional and cellular analysis of Aβ accumulation in 5XFAD mice, demonstrating the early development of neurodegenerative changes and their correlation with cognitive impairment (ref: Daini doi.org/10.1016/j.neulet.2021.135869/). Collectively, these studies underscore the multifaceted nature of neurodegeneration and cognitive impairment in AD, emphasizing the need for comprehensive approaches to address these challenges.