Microglia, the brain's resident immune cells, play a complex role in Alzheimer's disease (AD) pathology. Recent studies have highlighted the metabolic reprogramming of microglia in response to amyloid-beta (Aβ) accumulation. For instance, Lu et al. demonstrated that microglial energy metabolism is significantly suppressed during chronic Aβ exposure, affecting oxidative phosphorylation and aerobic glycolysis through the mTOR-AKT-HIF-1α pathway (ref: Lu doi.org/10.15252/embr.202052013/). This metabolic dysfunction may contribute to the overall inflammatory environment in AD. Furthermore, Schilling et al. explored the differential activation of microglia through Toll-like receptors (TLRs), revealing that TLR2 and TLR3 activation leads to varying levels of neuronal network dysfunction, indicating a context-dependent role of microglia in neuroinflammation (ref: Schilling doi.org/10.1016/j.bbi.2021.05.013/). In a genetic context, Quan et al. found that haploinsufficiency of MyD88 in microglia reduced Aβ load and improved cognitive function in APP/PS1-transgenic mice, suggesting that modulating microglial activation can ameliorate AD pathology (ref: Quan doi.org/10.1002/glia.24007/). Vautheny et al. further emphasized the importance of microglial signaling, showing that TREM2 deficiency exacerbates tau pathology in a mouse model, highlighting the critical role of microglial health in the progression of AD (ref: Vautheny doi.org/10.1016/j.nbd.2021.105398/). Lastly, El-Din et al. investigated the potential of rice bran extract as a PPAR-γ agonist to modulate microglial phenotype, suggesting a therapeutic avenue for addressing neuroinflammation in AD (ref: El-Din doi.org/10.1007/s11011-021-00741-4/).

Neuroinflammation is a hallmark of Alzheimer's disease, characterized by the activation of microglia and astrocytes. Alvarez-Vergara et al. highlighted the paradox of non-productive angiogenesis in the AD brain, where angiogenic markers are present, yet blood vessels are disassembled around Aβ plaques due to microglial phagocytosis (ref: Alvarez-Vergara doi.org/10.1038/s41467-021-23337-z/). This suggests that microglial activity not only contributes to inflammation but also affects vascular integrity in AD. In a translational context, Souder et al. proposed that rhesus monkeys serve as a more accurate model for late-onset AD, as they exhibit a more complex amyloid plaque microenvironment compared to rodent models, which may better reflect human disease pathology (ref: Souder doi.org/10.1111/acel.13374/). Aichholzer et al. investigated glycoprotein NMB (GPNMB) as a potential biomarker for AD, finding elevated levels in cerebrospinal fluid associated with neuroinflammatory changes, thus linking neuroinflammation to diagnostic markers (ref: Aichholzer doi.org/10.1186/s13195-021-00828-1/). Wittrahm et al. examined the role of MECP2 in enhancing the pro-inflammatory response of microglia, suggesting that its phosphorylation status may regulate neuroinflammatory responses in AD (ref: Wittrahm doi.org/10.3390/cells10040860/). Ji et al. discussed how aging exacerbates cognitive impairment following surgical trauma, indicating that neuroinflammatory responses may be heightened in older populations, further complicating AD pathology (ref: Ji doi.org/10.3233/JAD-201590/).

Therapeutic strategies for Alzheimer's disease are increasingly focusing on targeting specific pathological features such as tau pathology. Ayalon et al. reported on semorinemab, a humanized anti-tau monoclonal antibody that demonstrated efficacy in reducing tau pathology in a transgenic mouse model and engaged tau in early-phase clinical trials (ref: Ayalon doi.org/10.1126/scitranslmed.abb2639/). This highlights the potential of tau-targeted therapies in modifying disease progression. In addition, Vicente-Rodríguez et al. explored the utility of TSPO PET imaging as a biomarker for neuroinflammation, although challenges remain in interpreting the signals due to cellular heterogeneity (ref: Vicente-Rodríguez doi.org/10.1016/j.bbi.2021.05.025/). Li et al. introduced JWX-A0108, a positive allosteric modulator of α7 nAChR, which improved cognitive deficits in APP/PS1 mice by suppressing NF-κB-mediated inflammation, demonstrating the importance of anti-inflammatory strategies in AD treatment (ref: Li doi.org/10.1016/j.intimp.2021.107726/). Furthermore, Lee et al. presented NB-02, a botanical therapeutic that effectively addressed neuropathophysiology in an APP/PS1 mouse model, suggesting that natural compounds may offer novel treatment avenues (ref: Lee doi.org/10.1523/ENEURO.0389-20.2021/). These studies collectively underscore the diverse approaches being explored to mitigate AD pathology through targeted therapies.

Understanding the cellular and molecular mechanisms underlying Alzheimer's disease is crucial for developing effective interventions. Jin et al. introduced scGRNom, a computational pipeline for integrative multi-omics analyses that predicts cell-type-specific disease genes and regulatory networks, providing insights into the genetic underpinnings of AD (ref: Jin doi.org/10.1186/s13073-021-00908-9/). Kanaan et al. challenged the notion that tau is exclusively axon-specific, revealing its presence in somatodendritic compartments and glial cells in both rats and monkeys, which may have implications for understanding tau's role in AD pathology (ref: Kanaan doi.org/10.3389/fnmol.2021.607303/). Caruso et al. focused on the SIRT1-dependent upregulation of BDNF in microglia exposed to Aβ, highlighting an early but transient protective response that could be leveraged for therapeutic strategies (ref: Caruso doi.org/10.3390/biomedicines9050466/). Zhang et al. examined the effects of urban air pollution nanoparticles on neuroinflammation, finding a decrease in neurotoxic potency over time, which may inform environmental health strategies related to AD (ref: Zhang doi.org/10.3233/JAD-201577/). Lastly, He et al. explored the role of preventive electroacupuncture in ameliorating inflammation and cognitive deficits in aging rats, suggesting that non-pharmacological interventions could modulate neuroinflammatory pathways (ref: He doi.org/10.22038/ijbms.2021.49147.11256/).

Environmental factors play a significant role in the pathogenesis of Alzheimer's disease, with aging being a critical risk factor. Ji et al. highlighted how aging exacerbates cognitive impairments following surgical trauma, linking neuroinflammatory responses to postoperative cognitive disorders, particularly in the elderly (ref: Ji doi.org/10.3233/JAD-201590/). Naidu et al. discussed the neuroprotective effects of lactoferrin, emphasizing its role in maintaining blood-brain barrier integrity and its potential implications for mental health, especially in the context of neuro-COVID-19 (ref: Naidu doi.org/10.1080/19390211.2021.1922567/). Bocharova et al. investigated the interaction between β-amyloid and herpes simplex virus 1, finding that Aβ does not protect against viral infection in the brain, which raises questions about the interplay between infectious agents and AD pathology (ref: Bocharova doi.org/10.1016/j.jbc.2021.100845/). Shen et al. mapped gene expression profiles to spontaneous brain activity, identifying cell-type-specific gene modules that correlate with common brain disorders, thus providing a molecular basis for understanding environmental influences on AD (ref: Shen doi.org/10.3389/fnins.2021.639527/). Lastly, Wittrahm et al. noted that MECP2 phosphorylation affects microglial responses during neuroinflammation, suggesting that environmental factors could modulate these pathways (ref: Wittrahm doi.org/10.3390/cells10040860/).

Animal models are essential for understanding Alzheimer's disease mechanisms and testing therapeutic interventions. Souder et al. emphasized the importance of using rhesus monkeys as a translational model for late-onset AD, as they better replicate the human amyloid plaque microenvironment compared to traditional rodent models (ref: Souder doi.org/10.1111/acel.13374/). Lee et al. demonstrated the efficacy of the botanical therapeutic NB-02 in treating neuropathophysiology in an APP/PS1 mouse model, highlighting the potential of natural compounds in AD research (ref: Lee doi.org/10.1523/ENEURO.0389-20.2021/). Vautheny et al. reported that TREM2 deficiency in the THY-Tau22 mouse model leads to increased tau pathology at late disease stages, underscoring the role of microglial signaling in AD progression (ref: Vautheny doi.org/10.1016/j.nbd.2021.105398/). Ayalon et al. provided insights into the development of semorinemab, an anti-tau monoclonal antibody, in transgenic mouse models, illustrating the importance of tau-targeted therapies (ref: Ayalon doi.org/10.1126/scitranslmed.abb2639/). Lastly, El-Din et al. explored the effects of rice bran extract on microglial modulation in AD mice, suggesting that dietary interventions could influence disease outcomes (ref: El-Din doi.org/10.1007/s11011-021-00741-4/).