Microglial activation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), particularly in relation to tau pathology and amyloid-beta (Aβ) accumulation. Recent studies have demonstrated that microglia undergo a transformation into neurodegenerative microglia (MGnD) in response to amyloid plaque accumulation, which enhances their phagocytic activity towards plaques and apoptotic neurons. For instance, Clayton et al. found that plaque-associated microglia hyper-secrete extracellular vesicles that accelerate tau propagation in a humanized APP mouse model (ref: Clayton doi.org/10.1186/s13024-021-00440-9/). Furthermore, the role of specific microRNAs, such as miR-155, has been highlighted in modulating the inflammatory responses of microglia, suggesting that these molecules could be potential therapeutic targets (ref: Aloi doi.org/10.1002/glia.23988/). The complexity of microglial responses is further illustrated by the contrasting effects of different variants of the CD33 gene, where the Alzheimer's disease-protective variant CD33m enhances phagocytosis, while the CD33M variant inhibits it (ref: Butler doi.org/10.1111/jnc.15349/). This indicates a nuanced interplay between microglial activation and the progression of neurodegenerative processes in AD. In addition to the molecular characterization of microglial responses, studies have explored the therapeutic potential of targeting microglial pathways. Ramesha et al. identified Kv1.3 potassium channels as promising targets for modulating neuroinflammation, revealing that Kv1.3 blockade can reduce Aβ burden in mouse models (ref: Ramesha doi.org/10.1073/pnas.2013545118/). Moreover, the inhibition of nuclear factor-kappa B (NF-κB) signaling has emerged as a strategy to suppress neuroinflammation, with Lindsay et al. demonstrating that a specific peptide can reduce gliosis and innate immune receptor activation in transgenic mouse models of AD (ref: Lindsay doi.org/10.1016/j.biopha.2021.111405/). Collectively, these findings underscore the dual role of microglia in both promoting and mitigating neurodegenerative processes, emphasizing the need for targeted therapeutic strategies that can modulate their activity effectively.

Tau pathology is a critical feature of Alzheimer's disease, characterized by the accumulation of hyperphosphorylated tau protein within neurons. Recent research has focused on developing models to better understand tau's role in AD pathogenesis. Beckman et al. introduced a novel tau-based rhesus monkey model, which allows for the investigation of tau mutations and their effects on neurodegeneration (ref: Beckman doi.org/10.1002/alz.12318/). This model is particularly significant as it bridges the gap between rodent studies and human pathology, potentially leading to more translatable therapeutic strategies. Additionally, Bajracharya et al. explored the differential effects of tau antibody isotypes in passive immunization of tau transgenic mice, revealing that specific isotypes can engage and clear pathogenic tau forms, thus offering insights into immunotherapeutic approaches (ref: Bajracharya doi.org/10.1186/s40478-021-01147-0/). The interplay between tau pathology and neuroinflammation has also been a focal point of investigation. Fairley et al. examined the neuroprotective effects of mitochondrial translocator protein ligands in tau transgenic mice, finding that these ligands can mitigate tau-related neuropathology (ref: Fairley doi.org/10.1186/s12974-021-02122-1/). Furthermore, the concept of inflammation spreading, as discussed by Ni et al., highlights the negative feedback loop between systemic inflammatory disorders and AD, suggesting that systemic inflammation may exacerbate tau pathology (ref: Ni doi.org/10.3389/fncel.2021.638686/). Together, these studies illustrate the multifaceted nature of tau pathology in AD, emphasizing the need for integrated approaches that consider both tau and inflammatory mechanisms in therapeutic development.

Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer's disease, and its impact on synaptic function is a critical area of research. Kim et al. demonstrated that Aβ accumulation in the ventromedial orbitofrontal cortex contributes to masticatory dysfunction in 5XFAD mice, linking cognitive impairment to specific behavioral deficits (ref: Kim doi.org/10.1177/00220345211000263/). This study highlights the broader implications of Aβ pathology beyond cognitive decline, suggesting that Aβ may disrupt neural circuits involved in motor functions. Additionally, Davis et al. investigated the effects of pharmacological ablation of astrocytes on Aβ degradation and synaptic connectivity, revealing that such ablation leads to increased Aβ levels and reduced dendritic spine size in 5XFAD mice (ref: Davis doi.org/10.1186/s12974-021-02117-y/). This underscores the importance of astrocytic function in maintaining synaptic integrity in the context of Aβ pathology. Moreover, the role of maternal antibodies in Aβ clearance has been explored by Illouz et al., who found that maternal antibodies can activate phagocytosis mechanisms to facilitate Aβ clearance, presenting a potential therapeutic avenue for AD (ref: Illouz doi.org/10.1038/s42003-021-01851-6/). The study of paraoxonase proteins by Salazar et al. further elucidates the relationship between oxidative stress, inflammation, and Aβ pathology, as they observed intense expression of PON1 and PON3 around Aβ plaques in Tg2576 mice (ref: Salazar doi.org/10.3390/antiox10030339/). Collectively, these findings emphasize the complex interactions between Aβ accumulation, synaptic dysfunction, and neuroinflammation, highlighting the need for multifaceted therapeutic strategies targeting these interconnected pathways.

Therapeutic strategies targeting microglia have gained attention as potential interventions for Alzheimer's disease, particularly in modulating neuroinflammation. Potter et al. investigated the safety and efficacy of sargramostim (GM-CSF), a pro-inflammatory cytokine, in AD treatment. Their findings indicated that GM-CSF treatment led to increased activation of microglia, reduced amyloid load, and improved spatial memory in transgenic AD mice, suggesting that enhancing microglial activity may have beneficial effects in AD (ref: Potter doi.org/10.1002/trc2.12158/). This study challenges the traditional view of inflammation as solely detrimental, proposing that a controlled inflammatory response may be advantageous in combating AD pathology. In addition to GM-CSF, Kwon et al. explored the inhibition of SGK1 in glia, demonstrating that this approach ameliorates pathologies and symptoms in Parkinson's disease models, which may have implications for AD as well (ref: Kwon doi.org/10.15252/emmm.202013076/). Furthermore, the inhibition of NF-κB signaling by Lindsay et al. showed promise in suppressing neuroinflammation and gliosis in transgenic mouse models of AD, indicating that targeting specific inflammatory pathways could be a viable therapeutic strategy (ref: Lindsay doi.org/10.1016/j.biopha.2021.111405/). These studies collectively highlight the potential of microglia-targeted therapies in AD, emphasizing the need for further research to optimize these approaches for clinical application.

The genetic and molecular underpinnings of Alzheimer's disease are critical for understanding its pathogenesis and developing targeted therapies. Saito et al. utilized RNA-seq profiles from post-mortem AD brains to reveal alterations in glycolytic and ketolytic gene expression, suggesting that impaired brain metabolism may contribute to AD onset and progression (ref: Saito doi.org/10.1002/alz.12310/). This study highlights the importance of metabolic pathways in AD and opens avenues for exploring metabolic interventions as potential therapeutic strategies. Additionally, the role of NF-κB in driving neuroinflammation and neurodegeneration has been emphasized by Lindsay et al., who demonstrated that targeting activated NF-κB can suppress gliosis and innate immune receptor activation in AD models (ref: Lindsay doi.org/10.1016/j.biopha.2021.111405/). Furthermore, Zhao et al. investigated the role of P2X7 receptors in mediating neuroinflammation, revealing their involvement in neuronal functions and the potential for targeting these receptors in therapeutic strategies (ref: Zhao doi.org/10.3389/fnmol.2021.641570/). These findings underscore the complexity of genetic and molecular interactions in AD, suggesting that a multifaceted approach targeting various pathways may be necessary for effective treatment.

Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of Alzheimer's disease, with systemic inflammatory disorders potentially exacerbating neuroinflammatory responses. Ni et al. highlighted the negative spiral linking systemic inflammatory disorders and AD, discussing the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation (ref: Ni doi.org/10.3389/fncel.2021.638686/). This review emphasizes the need for a holistic understanding of inflammation in AD, suggesting that targeting systemic inflammation could have beneficial effects on neuroinflammation and disease progression. Salazar et al. further explored the relationship between oxidative stress and inflammation in AD, finding intense expression of paraoxonase proteins in the brains of Tg2576 mice, which are associated with Aβ plaques (ref: Salazar doi.org/10.3390/antiox10030339/). Additionally, Fu et al. demonstrated that isoliquiritigenin can alleviate Aβ-induced neuroinflammation in microglia by regulating the Nrf2/NF-κB signaling pathway, highlighting the potential for dietary compounds to modulate neuroinflammatory responses (ref: Fu doi.org/10.3389/fnins.2021.638772/). Together, these studies underscore the intricate relationship between systemic disorders and neuroinflammation in AD, suggesting that interventions targeting both systemic and central nervous system inflammation may be beneficial in managing the disease.

Microglial responses to amyloid and tau pathologies are critical in understanding the progression of Alzheimer's disease. Maeda et al. characterized distinct microglial responses against Aβ and tau pathologies, revealing that the transition from homeostatic to disease-associated microglia is marked by changes in gene expression, including the down-regulation of the P2Y12 receptor (ref: Maeda doi.org/10.1093/braincomms/). This finding underscores the importance of microglial activation states in the context of neurodegeneration and suggests that specific microglial phenotypes may play different roles in the progression of AD. Moreover, Butler et al. investigated the effects of CD33 variants on microglial function, demonstrating that the Alzheimer's disease-protective variant CD33m enhances phagocytosis and proliferation, while the CD33M variant inhibits these processes (ref: Butler doi.org/10.1111/jnc.15349/). This highlights the potential for genetic factors to influence microglial responses and their implications for AD pathology. Additionally, the study by Lindsay et al. on NF-κB inhibition further supports the notion that modulating microglial activation can have therapeutic benefits in AD, as it can suppress neuroinflammation and gliosis (ref: Lindsay doi.org/10.1016/j.biopha.2021.111405/). Collectively, these studies emphasize the critical role of microglia in responding to amyloid and tau pathologies, suggesting that targeted interventions aimed at modulating microglial activity could be a promising strategy for Alzheimer's disease treatment.