Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their interaction with amyloid-beta (Aβ) and tau pathologies. A study demonstrated that the levels of soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) are dynamic, showing a decrease in preclinical stages of AD associated with Aβ pathology, while an increase is observed with tau deposition and neurodegeneration (ref: Ma doi.org/10.1186/s13024-020-00374-8/). This suggests that TREM2 may serve as a biomarker for disease progression. Another study highlighted the potential of interleukin (IL)-33 to reprogram microglial transcriptomes, enhancing their phagocytic activity and reducing Aβ burden in transgenic mouse models (ref: Lau doi.org/10.1016/j.celrep.2020.107530/). Furthermore, the inhibition of formyl peptide receptors was shown to improve outcomes in mouse models by modulating glial cell function, indicating the therapeutic potential of targeting microglial receptors (ref: Schröder doi.org/10.1186/s12974-020-01816-2/). Overall, these findings underscore the importance of microglial function in AD and suggest that therapeutic strategies aimed at modulating microglial activity could be beneficial. In addition to receptor modulation, transcriptomic profiling of microglia and astrocytes has revealed significant age-related changes that may contribute to AD progression. A study found that specific age-related genes in these glial cells were consistently upregulated or downregulated from four months onward in AD mouse models, indicating a shift in their functional states with aging (ref: Pan doi.org/10.1186/s12974-020-01774-9/). Moreover, microRNA-22 was identified as a negative regulator of inflammatory factors in AD, suggesting that targeting this microRNA could mitigate neuroinflammation and improve cognitive function (ref: Han doi.org/10.1002/brb3.1627/). Collectively, these studies highlight the multifaceted roles of microglia in AD, emphasizing the need for further exploration of their functional states and regulatory mechanisms.

Neuroinflammation is a hallmark of Alzheimer's disease, with various cytokines playing pivotal roles in disease progression. A study identified the macrophage migration inhibitory factor (MIF) as a key mediator of neuroinflammation, showing that inhibition of MIF reduced cytokine production in both in vitro and in vivo models (ref: Nasiri doi.org/10.1186/s10020-020-00163-5/). This suggests that targeting MIF could be a viable therapeutic strategy for mitigating neuroinflammation in AD. Additionally, a multifunctional chemical agent was shown to attenuate amyloid burden and neuroinflammation, indicating that combined therapeutic approaches targeting multiple pathways may be necessary for effective AD treatment (ref: Cho doi.org/10.1021/acschemneuro.0c00114/). The role of neuronal signaling in neuroinflammation was further elucidated through a study examining spleen tyrosine kinase (SYK) in tau pathology. It was found that organotypic brain slices from transgenic Tau P301S mice exhibited increased cytokine production, which was significantly reduced upon SYK inhibition (ref: Schweig doi.org/10.1016/j.neulet.2020.134992/). This highlights the importance of SYK in mediating inflammatory responses in tau-related neurodegeneration. Furthermore, the study of cerebrospinal fluid (CSF) biomarkers revealed that YKL-40 and chitotriosidase levels were elevated in individuals with Alzheimer's pathology, suggesting their potential as biomarkers for disease progression and neuroinflammation (ref: Woollacott doi.org/10.1159/000506282/). Together, these findings underscore the complex interplay between neuroinflammation and cytokine regulation in Alzheimer's disease, pointing to potential therapeutic targets for intervention.

Recent proteomic analyses have significantly advanced our understanding of Alzheimer's disease pathophysiology, revealing early changes in energy metabolism associated with microglial and astrocyte activation. A large-scale study involving over 2,000 brain samples and nearly 400 cerebrospinal fluid samples identified specific proteins that could serve as potential biomarkers and therapeutic targets for AD (ref: Johnson doi.org/10.1038/s41591-020-0815-6/). This comprehensive approach highlights the importance of proteomic profiling in elucidating the molecular underpinnings of AD and identifying early biomarkers that could facilitate diagnosis and treatment. Additionally, the study of N-cadherin levels in CSF and brain homogenates provided insights into the structural changes occurring in AD. Elevated levels of cleaved N-cadherin were found in the CSF of AD patients compared to controls, suggesting its potential role as a biomarker for disease severity (ref: Choi doi.org/10.1093/jnen/). Furthermore, the impact of the amyloid-beta-rich environment on myeloid cell functionality was investigated, revealing that this pathological context alters the functional characteristics of both endogenous microglia and newly recruited peripheral myeloid cells (ref: Drost doi.org/10.1038/s41598-020-63989-3/). These findings emphasize the need for continued exploration of proteomic and biomarker studies to enhance our understanding of AD and improve therapeutic strategies.

Therapeutic strategies targeting microglia have gained traction in Alzheimer's disease research, particularly in light of their role in neuroinflammation and amyloid pathology. A study demonstrated that a selective p38α/β MAPK inhibitor, NJK14047, alleviated neuropathology and cognitive impairment in a 5XFAD mouse model of AD. Treatment with NJK14047 resulted in decreased Aβ deposits and improved spatial learning and memory, highlighting the therapeutic potential of modulating microglial function through MAPK inhibition (ref: Gee doi.org/10.1186/s13195-020-00617-2/). In addition to MAPK inhibition, the reprogramming of microglial transcriptomes through IL-33 administration was shown to enhance phagocytic activity and reduce Aβ pathology in transgenic mouse models (ref: Lau doi.org/10.1016/j.celrep.2020.107530/). Furthermore, the inhibition of formyl peptide receptors was associated with improved outcomes in mouse models, suggesting that targeting specific receptors on microglia could modulate their function and potentially alter disease progression (ref: Schröder doi.org/10.1186/s12974-020-01816-2/). These studies collectively indicate that therapeutic approaches aimed at microglial modulation may offer promising avenues for the treatment of Alzheimer's disease.

Age-related changes in microglia and astrocytes are critical factors in the progression of Alzheimer's disease. Transcriptomic profiling has revealed that activation of these glial cells is a hallmark of both aging and AD, with significant alterations in gene expression patterns observed as early as four months in AD mouse models (ref: Pan doi.org/10.1186/s12974-020-01774-9/). This study identified specific age-related genes that were consistently upregulated or downregulated, suggesting that aging influences the functional states of glial cells and their contributions to neurodegeneration. Moreover, the role of microRNA-22 in regulating neuroinflammation was explored, revealing a negative correlation between miRNA-22 expression and inflammatory factors in AD patients. This suggests that miRNA-22 may play a protective role by inhibiting the release of inflammatory cytokines, thereby improving cognitive function in AD models (ref: Han doi.org/10.1002/brb3.1627/). Together, these findings underscore the importance of understanding age-related changes in glial cells, as they may provide insights into the mechanisms underlying AD and potential therapeutic targets for intervention.

The triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a significant player in Alzheimer's disease pathology, particularly in relation to microglial function. A study demonstrated that dynamic changes in CSF sTREM2 levels correlate with different stages of AD, with decreased levels associated with Aβ pathology and increased levels linked to tau deposition and neurodegeneration (ref: Ma doi.org/10.1186/s13024-020-00374-8/). This suggests that TREM2 could serve as a biomarker for disease progression and highlights its role in modulating microglial responses to neurodegenerative processes. In addition to TREM2, the inhibition of formyl peptide receptors has been shown to improve outcomes in mouse models of AD, indicating that these receptors may also play a critical role in regulating glial cell function and neuroinflammation (ref: Schröder doi.org/10.1186/s12974-020-01816-2/). The interplay between these receptors and microglial activity underscores the potential for targeted therapies that modulate receptor signaling pathways to alter disease trajectories in Alzheimer's disease. Collectively, these findings emphasize the importance of understanding the roles of TREM2 and other receptors in the context of AD to develop effective therapeutic strategies.