Microglial activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD), with recent studies highlighting various mechanisms through which microglia contribute to neurodegeneration. One study demonstrated that histone H4 lysine 12 lactylation enhances microglial glucose metabolism, creating a positive feedback loop that exacerbates amyloid-beta (Aβ) accumulation and cognitive deficits in AD mouse models (ref: Pan doi.org/10.1016/j.cmet.2022.02.013/). Another investigation revealed that large extracellular vesicles released by microglia propagate early synaptic dysfunction, suggesting that these vesicles may serve as carriers of pathogenic signals that spread neurodegeneration throughout the brain (ref: Gabrielli doi.org/10.1093/brain/). Furthermore, the modulation of microglial inflammatory responses has been explored, with a lipoprotein-inspired nanoscavenger showing promise in enhancing Aβ clearance while mitigating microglial dysfunction (ref: Zhang doi.org/10.1021/acs.nanolett.2c00191/). In addition to these findings, the role of necroptosis in microglial activation has been emphasized, with evidence indicating that Aβ oligomers trigger necroptosis in neurons via microglial activation, leading to significant neurodegeneration (ref: Salvadores doi.org/10.1186/s40478-022-01332-9/). The microglial receptor TREM2 has also been implicated in promoting Aβ phagocytosis through exosome secretion, highlighting the importance of microglial exosomal pathways in AD (ref: Huang doi.org/10.1002/1873-3468.14336/). Lastly, the compound Arglabin has been shown to regulate microglial polarization, shifting the balance from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, thereby exerting neuroprotective effects (ref: Yang doi.org/10.1002/jbt.23045/). These studies collectively underscore the multifaceted roles of microglia in AD and suggest potential therapeutic targets for intervention.

Chronic neuroinflammation is increasingly recognized as a key driver of neurodegeneration and cognitive decline in Alzheimer's disease. One hypothesis posits that neuroinflammation directly contributes to synaptic and neuronal loss, as evidenced by the efficacy of 3,6'-dithioPomalidomide in reducing cognitive impairment in AD mouse models (ref: Lecca doi.org/10.1002/alz.12610/). Additionally, melanoma-secreted amyloid-beta has been shown to suppress neuroinflammation while promoting brain metastasis, indicating a complex interplay between cancer and neurodegenerative processes (ref: Kleffman doi.org/10.1158/2159-8290.CD-21-1006/). Moreover, innovative therapeutic strategies have emerged, such as metformin-based supramolecular nanodrugs that enhance microglial Aβ clearance, demonstrating a synergistic effect with existing treatments like donepezil (ref: Fan doi.org/10.1016/j.biomaterials.2022.121452/). The characterization of microglial markers such as Iba1, TMEM119, and P2RY12 has provided insights into the specific roles of microglia in AD pathology, revealing distinct expression patterns that correlate with disease progression (ref: Kenkhuis doi.org/10.1016/j.nbd.2022.105684/). Furthermore, Arglabin's ability to modulate microglial polarization highlights the potential for targeting neuroinflammation as a therapeutic approach (ref: Yang doi.org/10.1002/jbt.23045/). These findings collectively emphasize the critical role of neuroinflammation in AD and the need for targeted interventions to mitigate its effects.

The dynamics of amyloid-beta (Aβ) in Alzheimer's disease are central to understanding its pathophysiology and developing effective therapies. Recent research has introduced a 'Drug-Carrier' synergy therapy designed to simultaneously target Aβ and tau phosphorylation, showing promise in reducing AD pathology (ref: Han doi.org/10.1002/advs.202106072/). Additionally, the deficiency of microglial VPS35 has been linked to impaired Aβ phagocytosis and exacerbated Aβ-associated pathology, underscoring the importance of microglial function in Aβ clearance (ref: Ren doi.org/10.1186/s12974-022-02422-0/). Trilobatin has emerged as a neuroprotective agent, demonstrating the ability to rescue cognitive deficits in AD models by targeting the SIRT3/SOD2 signaling pathway (ref: Gao doi.org/10.1038/s41401-022-00888-5/). Furthermore, a multifunctional fluorescent probe has been developed for the visualization and detoxification of Aβ aggregates, showcasing its potential for both diagnostic and therapeutic applications (ref: Zhang doi.org/10.1039/d2cc00318j/). The compound 3',4',7-trihydroxyflavone has also been shown to downregulate neuroinflammatory responses in microglial cells, suggesting that anti-inflammatory strategies may enhance Aβ clearance (ref: Akaishi doi.org/10.1248/bpb.b21-00841/). Collectively, these studies highlight the multifaceted approaches being explored to target Aβ dynamics and improve therapeutic outcomes in Alzheimer's disease.

Microglial activation is closely associated with cognitive decline in Alzheimer's disease, with emerging evidence linking baseline microglial activation to amyloid pathology and cognitive outcomes. A study found that higher baseline microglial activation, as measured by [11C]PK11195 SUVR, predicted longitudinal cognitive decline in patients, suggesting that microglial activation may serve as a biomarker for disease progression (ref: Wang doi.org/10.1212/NXI.0000000000001152/). Additionally, the phenotypic characterization of microglia revealed distinct patterns associated with tau and amyloid pathology in the hippocampus, indicating that microglial responses may vary depending on the type of neurodegenerative pathology present (ref: Fixemer doi.org/10.1186/s40478-022-01342-7/). Moreover, interventions targeting microglial activation have shown promise in mitigating cognitive deficits. For instance, β-lactolin has been reported to improve mitochondrial function in Aβ-treated neuronal models, suggesting a potential therapeutic avenue for enhancing neuronal resilience against AD-related stressors (ref: Ayabe doi.org/10.1096/fj.202101366RR/). The modulation of CD38 expression in senescent microglia has also been linked to improved cognitive outcomes, highlighting the role of microglial metabolism and inflammatory responses in cognitive health (ref: Hu doi.org/10.1186/s40659-022-00379-1/). These findings collectively underscore the critical role of microglial activation in cognitive decline and the potential for targeted therapies to improve cognitive function in Alzheimer's disease.

Environmental factors, particularly air pollution, have been implicated in the pathogenesis of Alzheimer's disease, with recent studies exploring the mechanisms by which these factors influence neuroinflammation and amyloid pathology. One study demonstrated that ozone exposure disrupts the microenvironment surrounding Aβ plaques, impairing microglial function and leading to increased plaque load and neurodegeneration (ref: Greve doi.org/10.1093/brain/). This finding highlights the potential for environmental pollutants to exacerbate AD pathology through their effects on the brain's immune response. Additionally, the flavonoid nobiletin has shown potential in mitigating neuroinflammation in AD models, suggesting that dietary interventions may offer protective effects against environmental stressors (ref: Chai doi.org/10.1007/s11011-022-00932-7/). The modulation of microglial polarization by compounds such as Arglabin further emphasizes the importance of targeting neuroinflammatory pathways in response to environmental influences (ref: Yang doi.org/10.1002/jbt.23045/). These studies collectively underscore the need to consider environmental factors in the context of Alzheimer's disease and the potential for therapeutic strategies that address both biological and environmental contributors to disease progression.

The identification of reliable biomarkers for Alzheimer's disease is crucial for early diagnosis and monitoring disease progression. Recent studies have highlighted several promising candidates, including ABI3, which has been shown to decrease significantly in the serum and cerebrospinal fluid of AD patients, correlating with cognitive capacity (ref: Cao doi.org/10.3233/JAD-215635/). This suggests that ABI3 may serve as a novel early biomarker for AD detection. Chitinase-3-like protein 1 (CHI3L1/YKL-40) has also emerged as a significant biomarker, reflecting neuroinflammation and potentially aiding in the diagnosis of AD (ref: Connolly doi.org/10.1002/alz.12612/). Furthermore, the impaired experience-dependent refinement of place cells in a rat model of AD highlights the potential for neurophysiological measures to serve as biomarkers for cognitive decline (ref: Broussard doi.org/10.3233/JAD-215023/). These findings collectively emphasize the importance of developing a multifaceted approach to biomarker discovery, integrating molecular, physiological, and clinical data to enhance diagnostic accuracy in Alzheimer's disease.

Innovative therapeutic strategies are being developed to address the complex pathology of Alzheimer's disease, focusing on both symptomatic relief and disease modification. One promising approach is non-invasive photobiomodulation treatment, which has shown potential in improving cognitive deficits and neuronal health in transgenic rat models of AD (ref: Yang doi.org/10.7150/thno.70756/). This technique offers a novel avenue for therapeutic intervention without the need for invasive procedures. Additionally, meridianins have been identified as compounds that can rescue cognitive deficits and reduce neuroinflammation in AD models, highlighting the potential of targeting neuroinflammatory pathways as a therapeutic strategy (ref: Rodríguez-Urgellés doi.org/10.3389/fphar.2022.791666/). Furthermore, passive immunotherapy has demonstrated enhanced efficacy in reducing Aβ plaques in CD33-negative 5xFAD mice, suggesting that genetic modifications may improve therapeutic outcomes (ref: Gnoth doi.org/10.3390/biom12030399/). These studies collectively illustrate the diverse range of innovative strategies being explored to combat Alzheimer's disease, emphasizing the need for continued research into effective treatments.