Microglial activation and neuroinflammation are central to the pathogenesis of Alzheimer's disease (AD). Recent studies have highlighted the role of type I interferon (IFN-I) signaling in microglia and neural cells, revealing that IFN-I activation is robustly associated with amyloid beta (Aβ) pathology and contributes to memory impairment in murine models of AD (ref: Roy doi.org/10.1016/j.immuni.2022.03.018/). Additionally, amyloid-β has been shown to activate the NLRP3 inflammasome in microglia through the Syk-AMPK pathway, suggesting that targeting this pathway could mitigate neuroinflammation and its cognitive consequences (ref: Jung doi.org/10.1111/acel.13623/). In contrast, a study indicated that synthetic Aβ does not induce a significant transcriptional response in innate immune cell cultures, raising questions about the direct effects of Aβ on microglial activation (ref: Quiroga doi.org/10.1186/s12974-022-02459-1/). Furthermore, the activation of microglia in response to Aβ leads to the release of pro-inflammatory cytokines, which are implicated in cognitive decline (ref: Nillert doi.org/10.1186/s12906-022-03591-4/). Overall, these findings underscore the complexity of microglial responses to Aβ and the potential for therapeutic interventions targeting neuroinflammation in AD.

Understanding the genetic and molecular underpinnings of Alzheimer's disease (AD) is crucial for developing effective therapies. A comprehensive genome-wide association study identified 75 risk loci associated with AD, including 42 novel loci, which provides insights into the genetic landscape of the disease (ref: Bellenguez doi.org/10.1038/s41588-022-01024-z/). Additionally, allele-specific expression quantitative trait loci (aseQTLs) analysis revealed cell-type-specific regulatory effects of AD-associated genetic variants, emphasizing the importance of understanding these mechanisms in different brain regions and cell types (ref: He doi.org/10.1038/s41398-022-01913-1/). The role of neuroinflammation in AD is further supported by studies exploring the effects of various compounds on microglial activation and inflammatory pathways, such as Pomiferin and Huanglian Jiedu Decoction, which have shown promise in modulating neuroinflammation and improving cognitive function (ref: Zhao doi.org/10.1155/2022/; Qi doi.org/10.2147/DDDT.S357061/). These findings highlight the intricate relationship between genetic factors and neuroinflammatory processes in AD pathology.

Therapeutic strategies targeting microglial activation and neuroinflammation are gaining traction in Alzheimer's disease (AD) research. Prokineticin 2 (PK2) has emerged as a potential therapeutic target due to its role in neuroinflammation and its dual function as a chemokine, suggesting that modulating PK2 could influence microglial responses in neurodegenerative diseases (ref: Maftei doi.org/10.2174/1570159X20666220411084612/). Furthermore, Menthae Herba has demonstrated the ability to attenuate neuroinflammation by regulating the CREB/Nrf2/HO-1 pathway in microglial cells, indicating its potential as a natural therapeutic agent (ref: Park doi.org/10.3390/antiox11040649/). Curcumin and its analogues have also shown promise in modulating amyloid-β-induced microglial activation and neuronal cell death, highlighting their multi-faceted role in AD pathology (ref: De Lorenzi doi.org/10.3390/ijms23084381/). Collectively, these studies underscore the potential of targeting microglial pathways to develop effective treatments for AD.

Cytokines play a pivotal role in the immune response associated with Alzheimer's disease (AD), influencing microglial activation and neuroinflammation. Research has shown that interleukin-6 (IL-6) and interferon-alpha (IFN-α) induce distinct microglial phenotypes, leading to unique molecular adaptations that may contribute to the progression of neurodegenerative disorders (ref: West doi.org/10.1186/s12974-022-02441-x/). Additionally, amyloid-β has been implicated in the activation of the NLRP3 inflammasome in microglia, further linking neuroinflammation to AD pathology (ref: Jung doi.org/10.1111/acel.13623/). The interplay between cytokines and microglial responses is further complicated by the presence of aging-related epigenetic changes, which may exacerbate neuroinflammatory processes (ref: Stevenson doi.org/10.1111/ejn.15661/). These findings highlight the importance of understanding cytokine-mediated immune responses in the context of AD and their potential as therapeutic targets.

Amyloid beta (Aβ) is a central player in the pathology of Alzheimer's disease (AD), driving neuroinflammation and cognitive decline. Studies have demonstrated that Aβ activates type I interferon signaling pathways in microglia, which are associated with memory impairment in murine models (ref: Roy doi.org/10.1016/j.immuni.2022.03.018/). Furthermore, Aβ has been shown to activate the NLRP3 inflammasome in microglia, suggesting that targeting this pathway could mitigate the neuroinflammatory response linked to AD (ref: Jung doi.org/10.1111/acel.13623/). In contrast, some studies have indicated that certain natural compounds, such as Clausena harmandiana, can reduce Aβ accumulation and associated neuroinflammation, thereby improving cognitive function in AD models (ref: Nillert doi.org/10.1186/s12906-022-03591-4/). These findings underscore the dual role of Aβ in promoting neuroinflammation while also highlighting potential therapeutic avenues for mitigating its detrimental effects.

Age and sex differences significantly influence microglial function and their response to neurodegenerative processes in Alzheimer's disease (AD). Recent research has characterized the transcriptional landscape of human microglia, revealing that age, sex, and APOE genotype are critical factors affecting microglial activation and function (ref: Patel doi.org/10.1111/acel.13606/). This study identified a novel microglial signature associated with these variables, suggesting that therapeutic strategies may need to be tailored based on these demographic factors. Additionally, the peri-hematomal area in the brain has been identified as a strategic interface for blood clearance, indicating that microglial activity in this region may vary with age and could influence recovery from neuroinflammatory insults (ref: Puy doi.org/10.1161/STROKEAHA.121.037751/). These findings highlight the importance of considering age and sex in the context of microglial research and therapeutic development for AD.

Neuroprotective agents and natural compounds are being explored for their potential to mitigate the effects of Alzheimer's disease (AD) through modulation of neuroinflammation and oxidative stress. Prokineticin 2 (PK2) has been identified as a promising target due to its role in neuroinflammatory processes, suggesting that modulation of this chemokine could provide therapeutic benefits in AD (ref: Maftei doi.org/10.2174/1570159X20666220411084612/). Additionally, Menthae Herba has shown efficacy in attenuating neuroinflammation via the CREB/Nrf2/HO-1 pathway, indicating its potential as a natural therapeutic agent (ref: Park doi.org/10.3390/antiox11040649/). Curcumin and its analogues have also demonstrated the ability to modulate amyloid-β-induced microglial activation and neuronal cell death, further supporting the role of natural compounds in AD therapy (ref: De Lorenzi doi.org/10.3390/ijms23084381/). These studies collectively highlight the therapeutic potential of targeting neuroinflammatory pathways with natural compounds in the context of AD.

Microglial phenotypes play a crucial role in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Research has demonstrated that different cytokines, such as interleukin-6 (IL-6) and interferon-alpha (IFN-α), induce distinct microglial phenotypes, leading to unique molecular adaptations that can influence disease outcomes (ref: West doi.org/10.1186/s12974-022-02441-x/). Additionally, amyloid-β has been shown to activate the NLRP3 inflammasome in microglia, linking neuroinflammation to the activation of specific microglial phenotypes that may exacerbate neurodegeneration (ref: Jung doi.org/10.1111/acel.13623/). The interplay between microglial activation and neuroinflammatory responses is further complicated by aging-related epigenetic changes, which can alter microglial burdens and their functional states (ref: Stevenson doi.org/10.1111/ejn.15661/). These findings underscore the importance of understanding microglial phenotypes in the context of AD and their potential as therapeutic targets.