Microglial activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in the propagation of tau pathology. A study involving 130 individuals demonstrated that microglial activation and tau accumulation exhibit a Braak-like pattern, suggesting a spatial correlation in their progression (ref: Pascoal doi.org/10.1038/s41591-021-01456-w/). Additionally, the mitochondrial protein translocator protein (TSPO) has been implicated in AD, where its deficiency was shown to accelerate amyloid pathology and neuroinflammation by impairing microglial phagocytosis (ref: Zhang doi.org/10.1016/j.neurobiolaging.2021.06.020/). The interaction of microglial receptors, such as TREM2, is also significant; variants of TREM2 have been linked to increased risk for AD, as they modulate the uptake of modified amyloid-beta (Aβ) species, highlighting the importance of microglial function in Aβ clearance (ref: Joshi doi.org/10.1002/glia.24077/). Furthermore, elevated levels of microRNA-17 in AD microglia have been shown to inhibit autophagy-mediated Aβ degradation, indicating a potential mechanism for the accumulation of toxic Aβ species (ref: Estfanous doi.org/10.3389/fimmu.2021.705581/). In therapeutic contexts, azelastine has demonstrated anti-inflammatory effects in microglial cells by inhibiting the JNK/NF-κB pathway, suggesting a potential avenue for intervention in neuroinflammation (ref: Nguyen doi.org/10.3390/ijms22169061/). Lastly, the neuroprotective effects of palonosetron and methyllycaconitine were observed in a novel model of neuroinflammation, where they improved cognitive performance and reduced microglial activation (ref: Mohamed doi.org/10.3390/molecules26165068/).

The interplay between amyloid-beta (Aβ) and tau pathology is a central focus in Alzheimer's disease research. Lactoferrin, an acute phase protein, has been identified as a key feature of AD, influencing Aβ burden through the induction of amyloidogenic processing of the amyloid precursor protein (APP) (ref: Tsatsanis doi.org/10.1038/s41380-021-01248-1/). Chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis has been shown to promote neuroinflammation and tau hyperphosphorylation in a mouse model, underscoring the potential role of periodontal disease in AD pathogenesis (ref: Jiang doi.org/10.1016/j.bbi.2021.08.213/). In contrast, extracellular vesicles derived from inflammatory-educated stem cells have demonstrated the ability to reverse brain inflammation and improve cognitive function, suggesting a therapeutic potential in modulating neuroinflammatory responses (ref: Markoutsa doi.org/10.1016/j.ymthe.2021.08.008/). Additionally, deep learning techniques have been employed to quantitatively assess histopathological markers of AD, enhancing the reliability of neuropathological evaluations (ref: Perosa doi.org/10.1186/s40478-021-01235-1/). The consumption of green tea has been associated with reduced Aβ levels and cognitive impairment in mouse models, indicating dietary interventions may influence AD pathology (ref: Kan doi.org/10.1002/mnfr.202100626/). Furthermore, astragaloside IV has shown promise in ameliorating cognitive impairment and neuroinflammation in an oligomeric Aβ-induced mouse model, highlighting its potential as a therapeutic agent (ref: Chen doi.org/10.1248/bpb.b21-00381/).

Innovative therapeutic strategies are being explored to combat Alzheimer's disease, focusing on both pharmacological and dietary interventions. PLGA-PEG nanoparticles have been developed to enhance the bioavailability of fucoxanthin, a marine carotenoid with reported neuroprotective effects against AD (ref: Yang doi.org/10.1021/acs.jafc.1c00569/). Hydrolyzed chicken meat extract has also shown potential in attenuating neuroinflammation and cognitive decline in middle-aged mice by modulating microglial polarization (ref: Ni doi.org/10.1021/acs.jafc.1c03541/). The multi-target-directed ligand (MTDL) approach is gaining traction in the search for new AD treatments, leveraging traditional Chinese medicine to identify chemical constituents that can address multiple pathways involved in AD pathology (ref: Zhang doi.org/10.3389/fphar.2021.709607/). AZP2006, a novel treatment targeting progranulin levels, has emerged as a promising candidate for neurodegenerative diseases, emphasizing the need for strategies that enhance neuroprotective factors (ref: Callizot doi.org/10.1038/s41598-021-94708-1/). Additionally, machine learning approaches are being utilized to analyze cerebrospinal fluid proteomics, aiming to identify neuroinflammation biomarkers in AD, which could facilitate early diagnosis and treatment (ref: Gaetani doi.org/10.3390/cells10081930/).

Understanding the molecular mechanisms underlying Alzheimer's disease is critical for identifying potential biomarkers and therapeutic targets. A comparative analysis of microglial RNA-sequencing data revealed limited overlap in differentially expressed genes across studies, suggesting that experimental variations significantly influence findings (ref: van Wageningen doi.org/10.1002/glia.24078/). The acute phase protein lactoferrin has been highlighted as a predictor of Aβ burden, linking neuroinflammation to AD pathology through its role in APP processing (ref: Tsatsanis doi.org/10.1038/s41380-021-01248-1/). Furthermore, the development of deep learning models for the quantitative assessment of histopathological markers has improved the accuracy of AD diagnostics, addressing the variability associated with traditional visual assessments (ref: Perosa doi.org/10.1186/s40478-021-01235-1/). The exploration of spatial memory in chronic neuroinflammation models has revealed the impact of microglial activation on cognitive function, with potential therapeutic implications for compounds like apigenin that may mitigate these effects (ref: Chesworth doi.org/10.3389/fnins.2021.699329/). Additionally, the identification of key proteins associated with neuroinflammation through computational methods has provided insights into their regulatory microRNAs and pharmacological targetability, paving the way for novel therapeutic strategies (ref: El Idrissi doi.org/10.3389/fphar.2021.630003/).

Microglial function and gene expression are pivotal in the context of Alzheimer's disease, particularly in relation to neuroinflammation and amyloid pathology. Research has demonstrated that microglial activation is closely linked to the spread of tau tangles, with evidence suggesting that this activation follows a Braak-like pattern in the human brain (ref: Pascoal doi.org/10.1038/s41591-021-01456-w/). The role of TSPO in microglial function has been underscored by findings that its deficiency accelerates amyloid pathology and impairs phagocytosis, highlighting the importance of microglial health in AD (ref: Zhang doi.org/10.1016/j.neurobiolaging.2021.06.020/). Additionally, the interaction of TREM2 with modified Aβ species has been shown to influence microglial uptake and clearance, suggesting that genetic variations in TREM2 may affect individual susceptibility to AD (ref: Joshi doi.org/10.1002/glia.24077/). Elevated expression of microRNA-17 in AD microglia has been linked to impaired autophagy and Aβ degradation, indicating a potential target for therapeutic intervention (ref: Estfanous doi.org/10.3389/fimmu.2021.705581/). Furthermore, the characterization of RNA profiles in exosomes from glial cells has opened new avenues for understanding neurodegenerative mechanisms and the potential for exosome-based therapies (ref: Xie doi.org/10.4103/1673-5374.320999/).

Natural compounds are being increasingly recognized for their neuroprotective effects against Alzheimer's disease, with various studies highlighting their potential mechanisms of action. Fucoxanthin, a carotenoid derived from brown algae, has shown promise in mitigating AD pathology, particularly when delivered via PLGA-PEG nanoparticles to enhance its bioavailability in the central nervous system (ref: Yang doi.org/10.1021/acs.jafc.1c00569/). Green tea extract has also been investigated for its ability to suppress Aβ levels and alleviate cognitive impairment in mouse models, suggesting that dietary interventions may play a role in AD prevention (ref: Kan doi.org/10.1002/mnfr.202100626/). Astragaloside IV has demonstrated efficacy in ameliorating cognitive deficits and neuroinflammation in oligomeric Aβ-induced models, indicating its potential as a therapeutic agent (ref: Chen doi.org/10.1248/bpb.b21-00381/). The integration of traditional Chinese medicine through a multi-target approach has been proposed as a novel strategy for AD treatment, emphasizing the need for compounds that can address multiple pathways involved in the disease (ref: Zhang doi.org/10.3389/fphar.2021.709607/). Overall, these findings underscore the importance of exploring natural compounds for their neuroprotective properties and their potential application in therapeutic strategies against Alzheimer's disease.