Recent research has underscored the pivotal role of microglia in the pathogenesis of Alzheimer's Disease (AD), particularly in relation to neuroinflammation and tau pathology. A study by Jain et al. highlights the involvement of TREM2 and microglial exosomes in the spread of pathological tau, suggesting that the microglial endolysosomal system is crucial for tau transmission between neurons (ref: Jain doi.org/10.1186/s13024-022-00581-5/). Szego et al. further elucidate the neuroinflammatory consequences of STING pathway activation, demonstrating that a constitutively active STING variant leads to degeneration of dopaminergic neurons, indicating a broader implication of neuroinflammation in neurodegenerative diseases (ref: Szego doi.org/10.7554/eLife.81943/). Additionally, Fernández-Albarral et al. reveal that deletion of microglial heme oxygenase-1 reduces retinal inflammation in tauopathy models, linking microglial activity to neuroinflammatory processes in aging and AD (ref: Fernández-Albarral doi.org/10.3390/antiox11112151/). Moreover, Huang et al. demonstrate that sinapic acid can mitigate neuroinflammation by targeting AKT and MAPK pathways in LPS-activated microglial models, suggesting potential therapeutic avenues for reducing microglial activation in AD (ref: Huang doi.org/10.4062/biomolther.2022.092/). Shi et al. explore the relationship between cerebrospinal fluid ferritin and soluble TREM2, indicating that iron accumulation may exacerbate neuroinflammation and contribute to AD progression (ref: Shi doi.org/10.3389/fneur.2022.961842/). Collectively, these studies illuminate the complex interplay between microglial function, neuroinflammation, and the progression of Alzheimer's Disease.

The molecular landscape of Alzheimer's Disease is increasingly understood through advanced techniques such as single-cell transcriptomics and multi-omics data integration. Su et al. present a comprehensive single-nucleus RNA sequencing study that maps glial diversity in the human hippocampus, revealing distinct molecular signatures associated with age and disease, thereby providing insights into the cellular dynamics of AD (ref: Su doi.org/10.1016/j.stem.2022.09.010/). Garcia-Segura et al. contribute to this understanding by identifying lipidomic alterations in an AD mouse model, linking specific lipid signatures to genetic risk factors associated with late-onset AD, and highlighting the significance of lipid metabolism in disease pathology (ref: Garcia-Segura doi.org/10.1111/jnc.15719/). Furthermore, Jung et al. investigate the dysregulation of sphingosine-1-phosphate signaling in the 5xFAD mouse model, demonstrating that treatment with fingolimod can reverse pathological changes in S1P signaling pathways, which are implicated in tau phosphorylation and neurodegeneration (ref: Jung doi.org/10.1016/j.brainres.2022.148171/). Li et al. examine the role of amyloid precursor-like proteins in spinal GABAergic neurons, revealing that reduced APLP2 expression contributes to microglial activation and pain sensitization, thus linking molecular mechanisms to neuroinflammatory responses (ref: Li doi.org/10.1016/j.neuropharm.2022.109334/). These findings collectively enhance our understanding of the molecular mechanisms underlying Alzheimer's Disease and suggest potential therapeutic targets.

Neuroinflammation has emerged as a critical factor influencing cognitive function in Alzheimer's Disease, with gender differences further complicating this relationship. Islam et al. explore the correlation between microglial TLR4 and LYN expression in male and female 5XFAD mice, finding that increased co-localization of these markers is associated with AD pathogenesis, particularly in females (ref: Islam doi.org/10.1002/jcp.30916/). This suggests that gender-specific microglial responses may play a role in the differential progression of AD symptoms. In a therapeutic context, Sharma et al. highlight the challenges of treating chronic neuroinflammation, which is linked to various neurodegenerative diseases, including AD. Their work emphasizes the need for effective treatments that can cross the blood-brain barrier to mitigate neuroinflammation (ref: Sharma doi.org/10.1021/acschemneuro.2c00365/). Additionally, Lv et al. demonstrate that the PPM1A activator Miltefosine can improve AD-like pathology in mice, suggesting that modulating microglial-neuronal crosstalk may be a viable strategy for cognitive enhancement in AD (ref: Lv doi.org/10.1016/j.bbih.2022.100546/). Farhangian et al. further support this notion, showing that intranasal interferon-beta can alleviate anxiety and depressive-like behaviors in an AD model by promoting microglial M2 polarization, thereby enhancing cognitive function (ref: Farhangian doi.org/10.1016/j.neulet.2022.136968/). Together, these studies underscore the intricate relationship between neuroinflammation and cognitive function in Alzheimer's Disease.

Research into neurodegenerative disease models has revealed significant insights into potential therapeutic strategies for Alzheimer's Disease. Zhang et al. investigate the effects of hawthorn flavonoids on cognitive deficits in AD mice, demonstrating that these compounds can restore gut microbiota balance and metabolic profiles, suggesting a novel approach to AD treatment through dietary interventions (ref: Zhang doi.org/10.1039/d2fo02871a/). Sandor et al. identify neuroinflammation as a major factor influencing clinical variability in Parkinson's disease, drawing parallels with AD and emphasizing the role of microglial activation in disease progression (ref: Sandor doi.org/10.1186/s13073-022-01132-9/). Mosalam et al. explore the neuroprotective effects of verapamil against lipopolysaccharide-induced neuroinflammation, highlighting its potential as a therapeutic agent in AD (ref: Mosalam doi.org/10.1186/s10020-022-00564-8/). Lee et al. examine the impact of renal ischemia-reperfusion on neuroinflammation, revealing that microglial and astrocytic activation in the brain can exacerbate neurodegenerative processes, thus linking systemic health to neurological outcomes (ref: Lee doi.org/10.3390/biomedicines10112993/). Finally, Li et al. demonstrate that inhibition of circ_0004381 can improve cognitive function in AD models by promoting microglial M2 polarization, suggesting that targeting non-coding RNAs may offer new therapeutic avenues (ref: Li doi.org/10.1093/jnen/). Collectively, these studies highlight the importance of understanding neurodegenerative disease models to identify effective therapeutic strategies for Alzheimer's Disease.

Gender differences in the pathophysiology of Alzheimer's Disease are increasingly recognized, particularly in the context of microglial responses. The work of Rossi et al. from the pre-symposium of the 15th International Conference on Alzheimer's and Parkinson's Diseases emphasizes the importance of resilience and resistance to AD pathology, suggesting that gender may influence these mechanisms (ref: Rossi doi.org/10.1186/s13024-022-00571-7/). This aligns with findings from Katsumoto et al., who investigate the role of TREM2 in exacerbating inflammation following traumatic brain injury, highlighting the differential microglial activation patterns that may contribute to gender-specific disease outcomes (ref: Katsumoto doi.org/10.3389/fimmu.2022.978423/). Furthermore, Farhangian et al. explore how intranasal interferon-beta treatment can modulate microglial polarization in a rat model of AD, revealing that such interventions may have varying effects based on gender (ref: Farhangian doi.org/10.1016/j.neulet.2022.136968/). These studies collectively underscore the necessity of considering gender as a critical factor in understanding microglial responses and developing targeted therapies for Alzheimer's Disease.

External factors significantly influence neuroinflammation and its role in Alzheimer's Disease, as evidenced by recent studies. Zhu et al. investigate the impact of Aβ fibrils on the transcriptome of primary astrocytes and microglia, revealing that different fibril structures can trigger distinct cellular responses, thereby contributing to the complexity of AD pathology (ref: Zhu doi.org/10.3390/biomedicines10112982/). This highlights the need to understand how external amyloid structures can modulate neuroinflammatory responses in the brain. Additionally, Li et al. examine the role of amyloid precursor-like proteins in spinal GABAergic neurons, demonstrating that reduced APLP2 expression can lead to microglial activation and pain sensitization, linking external factors to neuroinflammatory processes (ref: Li doi.org/10.1016/j.neuropharm.2022.109334/). Garcia-Segura et al. further support this notion by identifying lipidomic alterations in an AD mouse model, suggesting that external metabolic factors may also play a role in neuroinflammation (ref: Garcia-Segura doi.org/10.1111/jnc.15719/). Together, these findings emphasize the multifaceted impact of external factors on neuroinflammation and their implications for Alzheimer's Disease.