Microglial dysfunction is increasingly recognized as a critical factor in the pathology of Alzheimer's disease (AD). Studies have identified specific genetic variants, such as those in TREM2 and PLCG2, that are associated with altered microglial function. For instance, research demonstrated that TREM2 signals through PLCG2 to facilitate microglial survival, phagocytosis, and lipid metabolism, highlighting its role as a signaling node in human microglia (ref: Andreone doi.org/10.1038/s41593-020-0650-6/). Additionally, the loss of the small GTPase Rhoa in microglia was shown to trigger spontaneous activation, leading to neurodegeneration characterized by synapse loss and memory deficits, underscoring the importance of Rhoa in maintaining microglial homeostasis (ref: Socodato doi.org/10.1016/j.celrep.2020.107796/). Proteomic analyses have further revealed that fibrillar Aβ induces significant alterations in the microglial proteome, with distinct changes observed at various stages of Aβ deposition, indicating a complex relationship between microglial activation and AD progression (ref: Sebastian Monasor doi.org/10.7554/eLife.54083/). Moreover, interventions aimed at restoring microglial function have shown promise in AD models. For example, intraperitoneal injection of IFN-γ was found to enhance autophagy and promote Aβ clearance, leading to improved cognitive outcomes in APP/PS1 mice (ref: He doi.org/10.1038/s41419-020-2644-4/). This suggests that targeting microglial pathways could be a viable therapeutic strategy. Conversely, the study of inflammatory markers in cerebrospinal fluid has revealed downregulation of synapse-associated proteins in both delirium and AD, indicating a shared neuroinflammatory response that may contribute to cognitive decline (ref: Peters van Ton doi.org/10.1016/j.bbi.2020.06.027/). Overall, these findings emphasize the multifaceted role of microglia in AD pathology and the potential for therapeutic interventions that modulate their function.

Neuroinflammation plays a pivotal role in the progression of Alzheimer's disease, with various cytokines and immune mediators influencing disease outcomes. For instance, the cytokine IFN-γ has been shown to restore microglial autophagy and enhance Aβ clearance, thereby improving cognitive function in AD mouse models (ref: He doi.org/10.1038/s41419-020-2644-4/). This highlights the potential of targeting immune responses to mitigate neurodegeneration. Additionally, the production of 25-hydroxycholesterol (25-HC) by microglia was found to be significantly elevated in the presence of the apoE4 allele, a known genetic risk factor for AD, suggesting that lipid metabolism may exacerbate inflammatory responses in AD (ref: Wong doi.org/10.1186/s12974-020-01869-3/). Moreover, the overexpression of CCL2 in the brain has been linked to accelerated tau pathology and glial activation, indicating that inflammatory mediators can directly influence the progression of tau-related neurodegeneration (ref: Joly-Amado doi.org/10.3389/fimmu.2020.00997/). The heterogeneity of microglial activation in response to neuroinflammatory stimuli has also been documented, with distinct patterns observed in different brain regions following ischemic injury (ref: Radenovic doi.org/10.18632/aging.103411/). These findings collectively underscore the complex interplay between neuroinflammation and immune responses in AD, suggesting that modulating these pathways could offer therapeutic benefits. Furthermore, natural compounds such as α-mangostin have demonstrated the ability to inhibit LPS-induced microglial activation, providing a potential avenue for anti-inflammatory therapies in AD (ref: Guan doi.org/10.1002/mnfr.202000096/).

The exploration of molecular mechanisms underlying Alzheimer's disease has revealed several potential therapeutic targets. Notably, the depletion of natural killer (NK) cells in a triple-transgenic AD mouse model was shown to alleviate neuroinflammation and enhance cognitive function, suggesting that immune modulation could be a promising strategy for AD treatment (ref: Zhang doi.org/10.4049/jimmunol.2000037/). Additionally, the upregulation of cathepsins in the olfactory bulbs of mice with experimental autoimmune encephalomyelitis was associated with transient olfactory dysfunction, indicating that these proteases may play a role in neuroinflammatory processes (ref: Kim doi.org/10.1007/s12035-020-01952-z/). Furthermore, the accumulation of tau-immunoreactive granules in aging brains highlights the involvement of reactive glia in tau pathogenesis, suggesting that targeting glial activation could mitigate tau-related neurodegeneration (ref: Wander doi.org/10.1016/j.isci.2020.101255/). The study of amyloid-β plaques in the context of cerebral amyloid angiopathy has also revealed that advanced stages of this condition may be associated with reduced plaque burden, complicating the understanding of amyloid pathology in aging (ref: Okamoto doi.org/10.1111/neup.12662/). These insights into the molecular underpinnings of AD emphasize the need for continued research into novel therapeutic approaches that target both immune and neurodegenerative pathways.

Genetic and environmental factors significantly influence the risk and progression of Alzheimer's disease. The loss of Rhoa in microglia has been shown to disrupt neuronal physiology and lead to neurodegeneration, highlighting the critical role of genetic factors in maintaining microglial function (ref: Socodato doi.org/10.1016/j.celrep.2020.107796/). Additionally, the expression of CH25H, which is upregulated in AD brain tissue, suggests that genetic predispositions, such as the presence of the apoE4 allele, can modulate inflammatory responses in microglia (ref: Wong doi.org/10.1186/s12974-020-01869-3/). Moreover, the interplay between genetic factors and environmental triggers, such as inflammation, is crucial in understanding AD pathology. For instance, the study of microglial activation in response to environmental stressors has revealed that specific genetic backgrounds can influence the severity of neuroinflammation and subsequent cognitive decline (ref: Nguyen doi.org/10.1002/glia.23847/). This underscores the importance of considering both genetic predispositions and environmental influences when developing therapeutic strategies for AD. Overall, these findings highlight the complexity of AD etiology and the need for personalized approaches that account for individual genetic and environmental contexts.

Microglial activation is a central feature of neurodegeneration in Alzheimer's disease, with various studies elucidating the mechanisms by which activated microglia contribute to neuronal loss. For example, the loss of Rhoa in microglia has been shown to lead to spontaneous activation, resulting in synapse and neuron loss, as well as the formation of amyloid plaques (ref: Socodato doi.org/10.1016/j.celrep.2020.107796/). Additionally, the proteomic analysis of microglia in mouse models of AD has revealed significant alterations in response to fibrillar Aβ, indicating that microglial dysfunction is not only a consequence but also a driver of neurodegeneration (ref: Sebastian Monasor doi.org/10.7554/eLife.54083/). Furthermore, the restoration of microglial autophagy through IFN-γ treatment has been shown to promote Aβ clearance and improve cognitive function in AD models, suggesting that enhancing microglial function could be a viable therapeutic approach (ref: He doi.org/10.1038/s41419-020-2644-4/). The role of inflammatory mediators, such as IL-1β, produced by activated microglia, has also been implicated in exacerbating neurodegeneration, particularly in the context of genetic risk factors like apoE4 (ref: Wong doi.org/10.1186/s12974-020-01869-3/). These findings collectively emphasize the dual role of microglia in AD as both protectors and aggressors, highlighting the complexity of targeting microglial activation for therapeutic benefit.

Cytokines and inflammatory mediators play a crucial role in the pathophysiology of Alzheimer's disease, influencing both neuroinflammation and neurodegeneration. For instance, the overexpression of CCL2 has been shown to exacerbate tau pathology and promote glial activation, indicating that inflammatory signals can directly impact the progression of neurodegenerative processes (ref: Joly-Amado doi.org/10.3389/fimmu.2020.00997/). Additionally, the cytokine IFN-γ has been demonstrated to restore microglial autophagy and enhance amyloid-β clearance, thereby improving cognitive outcomes in AD mouse models (ref: He doi.org/10.1038/s41419-020-2644-4/). Moreover, the biophysical mechanisms underlying microglial activation have been explored, with studies linking Kv1.3 regulation to P2X4-mediated calcium entry, which is crucial for microglial inflammatory responses (ref: Nguyen doi.org/10.1002/glia.23847/). The upregulation of cathepsins in the olfactory bulbs of mice with experimental autoimmune encephalomyelitis further illustrates the involvement of inflammatory mediators in neuroinflammatory responses (ref: Kim doi.org/10.1007/s12035-020-01952-z/). These findings underscore the importance of targeting cytokine signaling pathways as a potential therapeutic strategy for modulating neuroinflammation and mitigating cognitive decline in Alzheimer's disease.