Microglia, the resident immune cells of the central nervous system, play a crucial role in the pathogenesis of Alzheimer's disease (AD). Recent studies have highlighted the influence of the commensal microbiota on microglial function, revealing that alterations in microbiota can affect myeloid cell composition and function in the CNS (ref: Sankowski doi.org/10.15252/embj.2021108605/). Furthermore, the OAS1 gene has been identified as a genetic risk factor for AD, with its variant linked to increased microglial activity and susceptibility to neurodegeneration (ref: Magusali doi.org/10.1093/brain/). The relationship between microglia and tau pathology has also been elucidated, showing that microgliosis correlates with tau spread in a Braak-like pattern, suggesting that microglial activation may facilitate tau propagation (ref: Rossano doi.org/10.1016/j.tins.2021.10.002/). Additionally, microglia have been shown to regulate levels of progranulin, a protein associated with neurodegenerative diseases, through endocytosis and lysosomal pathways (ref: Dong doi.org/10.1172/jci.insight.136147/). The role of TREM2 in modulating amyloid-beta deposition further emphasizes the importance of microglial activity in AD pathology (ref: Joshi doi.org/10.1186/s40478-021-01263-x/). Moreover, peripheral inflammation has been found to exacerbate brain pathology in AD models, indicating that systemic immune responses can influence neuroinflammatory processes (ref: Xie doi.org/10.1186/s40478-021-01253-z/). Overall, these findings underscore the multifaceted role of microglia in AD, linking genetic, environmental, and inflammatory factors to disease progression.

Neuroinflammation is a pivotal aspect of Alzheimer's disease, with innate immune responses significantly contributing to disease pathology. Recent research has identified phospholipase Cγ2 as a key regulator of endocannabinoid and eicosanoid networks in innate immune cells, linking lipid metabolism to neuroinflammatory processes (ref: Jing doi.org/10.1073/pnas.2112971118/). Astrocytes have also been shown to enhance microglial responses to amyloid-beta through interleukin-3 signaling, suggesting a collaborative role in clearing neurotoxic aggregates (ref: Klein doi.org/10.1016/j.it.2021.09.008/). Furthermore, pharmacological interventions targeting neuroinflammation, such as QTC-4-MeOBnE, have demonstrated potential in alleviating cognitive impairments and neuroinflammatory responses in models of depression and AD (ref: Fronza doi.org/10.1016/j.bbi.2021.10.002/). The interplay between neuroinflammation and cognitive decline is further illustrated by studies on donepezil, which has been shown to regulate neuroinflammatory responses and improve cognitive function in AD models (ref: Kim doi.org/10.3390/ijms221910637/). Additionally, gut microbiota interactions with microglia have been implicated in AD pathology, highlighting the importance of the gut-brain axis in modulating neuroinflammatory responses (ref: Wang doi.org/10.1186/s13195-021-00917-1/). Collectively, these findings emphasize the critical role of neuroinflammation in Alzheimer's disease and suggest that targeting immune pathways may offer therapeutic avenues for intervention.

The genetic landscape of Alzheimer's disease is complex, with numerous studies identifying key genes and variants associated with increased risk. The OAS1 gene has emerged as a significant contributor to AD risk, particularly through its expression in microglia, linking genetic predisposition to neuroinflammatory processes (ref: Magusali doi.org/10.1093/brain/). Additionally, deep post-GWAS analyses have uncovered potential risk genes and variants, providing insights into the multifactorial nature of AD and its underlying mechanisms (ref: Wang doi.org/10.1038/s41598-021-99352-3/). Research has also explored the role of microglial-expressed ApoE in AD, revealing that its absence does not significantly alter plaque pathogenesis, suggesting that microglial function may be more nuanced than previously thought (ref: Henningfield doi.org/10.1002/glia.24105/). Furthermore, studies have identified common and distinct dysregulated pathways across various cell types in AD, highlighting the importance of understanding cell-specific responses to neurodegeneration (ref: Wang doi.org/10.1186/s12883-021-02407-1/). These findings underscore the intricate genetic and molecular interactions that contribute to Alzheimer's disease pathology and the necessity for targeted research in this domain.

The search for effective therapeutic strategies for Alzheimer's disease has led to the exploration of various compounds with neuroprotective properties. Recent studies have highlighted the potential of isoflavone derivatives, such as SPA1413, which exhibit strong inhibitory effects on amyloid-beta fibrilization and oligomerization, suggesting a promising avenue for AD treatment (ref: An doi.org/10.1111/bph.15691/). Cycloastragenol has also shown efficacy in regulating oxidative stress and neuroinflammation, indicating its potential as a therapeutic agent in neurodegenerative conditions (ref: Ikram doi.org/10.3390/cells10102719/). Moreover, the role of neuroinflammation in AD has prompted investigations into the effects of various compounds on microglial activation and amyloid-beta deposition. For instance, ceftriaxone has been demonstrated to reduce amyloid burden and improve cognitive function in AD models, highlighting its neuroprotective capabilities (ref: Tikhonova doi.org/10.3389/fnins.2021.736786/). Additionally, traditional medicines, such as Byur dMar Nyer lNga Ril Bu, have shown promise in enhancing cognitive abilities in AD mouse models, suggesting that integrative approaches may be beneficial (ref: Tsering doi.org/10.1016/j.jep.2021.114724/). These findings collectively emphasize the importance of developing multifaceted therapeutic strategies that address both neuroinflammation and amyloid pathology in Alzheimer's disease.

The gut-brain axis has emerged as a critical area of research in understanding Alzheimer's disease, with studies indicating that gut microbiota can significantly influence neuroinflammatory processes and cognitive function. Recent findings suggest that abnormal microglial function is closely associated with AD pathology, with specific microbial metabolites, such as short-chain fatty acids, playing a pivotal role in modulating neuroinflammation (ref: Wang doi.org/10.1186/s13195-021-00917-1/). Furthermore, low-grade peripheral inflammation has been shown to exacerbate brain pathology in AD, indicating that systemic immune responses can impact neurodegeneration (ref: Xie doi.org/10.1186/s40478-021-01253-z/). Additionally, traditional Tibetan medicine has been investigated for its effects on cognitive impairment in AD models, revealing that it may enhance cognitive abilities through mechanisms involving neuroinflammation and gut microbiota regulation (ref: Tsering doi.org/10.1016/j.jep.2021.114724/). These studies underscore the importance of considering the gut-brain axis in AD research and highlight the potential for microbiota-targeted interventions to mitigate neuroinflammation and cognitive decline.

Cognitive impairment in Alzheimer's disease has been extensively studied through various behavioral assessments in animal models. For instance, the Morris water maze and novel object recognition tests have been utilized to evaluate cognitive abilities in APP/PS1 transgenic mice, revealing significant deficits that can be ameliorated by interventions such as Gardenia jasminoides extract (ref: Zang doi.org/10.1016/j.phymed.2021.153780/). Additionally, compounds like cycloastragenol have demonstrated the ability to enhance memory and reduce neuroinflammatory responses, further supporting their potential as therapeutic agents (ref: Ikram doi.org/10.3390/cells10102719/). Moreover, the effects of traditional medicines, such as Byur dMar Nyer lNga Ril Bu, have shown promise in improving cognitive abilities in AD mouse models, indicating that alternative therapies may offer beneficial outcomes (ref: Tsering doi.org/10.1016/j.jep.2021.114724/). These findings highlight the importance of behavioral studies in understanding the cognitive deficits associated with Alzheimer's disease and the potential for various interventions to improve cognitive function.

The pathological features of Alzheimer's disease are characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles, with neuroinflammation playing a significant role in disease progression. Recent studies have demonstrated that astrocyte-derived interleukin-3 enhances microglial capacity to clear amyloid-beta oligomers, suggesting a collaborative mechanism in managing amyloid pathology (ref: Klein doi.org/10.1016/j.it.2021.09.008/). Additionally, low-grade peripheral inflammation has been shown to impact brain pathology in AD, indicating that systemic inflammatory responses can exacerbate neurodegeneration (ref: Xie doi.org/10.1186/s40478-021-01253-z/). Research has also focused on the localization of GPR39 in the aging human brain, revealing its expression in microglia and its potential association with vascular cognitive impairment, further linking pathological features to cognitive decline (ref: Davis doi.org/10.1002/trc2.12214/). Furthermore, cell type-specific analyses have identified dysregulated pathways and genes associated with AD, emphasizing the complexity of the disease's pathology and the need for targeted research to unravel these mechanisms (ref: Wang doi.org/10.1186/s12883-021-02407-1/). These findings collectively enhance our understanding of the pathological features of Alzheimer's disease and their implications for therapeutic strategies.