Microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly through their interactions with amyloid-beta (Aβ) and tau pathology. A study identified a rare protective variant in the PLCG2 gene, which is highly expressed in microglia, showing that this variant is associated with reduced cognitive decline in patients with mild cognitive impairment (ref: Kleineidam doi.org/10.1007/s00401-020-02138-6/). This suggests that enhancing microglial function could be a potential therapeutic strategy. Another study demonstrated that β-amyloid clustering around ASC fibrils exacerbates microglial toxicity, indicating that microglial activation by Aβ is a double-edged sword, potentially leading to neuroinflammation and neurodegeneration (ref: Friker doi.org/10.1016/j.celrep.2020.02.025/). Furthermore, the modulation of TREM2, a receptor critical for microglial activation, has been shown to enhance protective microglial activities, emphasizing the importance of microglial signaling pathways in AD (ref: Schlepckow doi.org/10.15252/emmm.201911227/). The depletion of microglia has been linked to disrupted development of adult-born neurons, suggesting that microglia are essential not only in disease states but also in maintaining normal neurogenesis (ref: Wallace doi.org/10.7554/eLife.50531/). Overall, these findings highlight the complex role of microglia in both the progression and potential treatment of AD, with implications for targeting microglial pathways to mitigate disease progression.

Neuroinflammation is a hallmark of Alzheimer's disease, with cytokines playing a pivotal role in the inflammatory response. A study explored the relationship between peripheral cytokines and neuroinflammation in AD and amnestic mild cognitive impairment (aMCI) patients, revealing elevated levels of IL-6 and IL-10 in AD patients compared to healthy controls (ref: Cisbani doi.org/10.1016/j.bbi.2020.02.014/). This suggests that systemic inflammation may correlate with neuroinflammatory processes in the brain. Additionally, the rhamnoside PL201 was shown to alleviate neuroinflammation and stimulate Nrf2 signaling, indicating that targeting inflammatory pathways could be beneficial in AD treatment (ref: An doi.org/10.3389/fimmu.2020.00162/). The immunoproteasome inhibitor LMP2 has also been implicated in modulating neuroinflammation, with studies showing that its inhibition can improve cognitive functions in AD models (ref: Bhattarai doi.org/10.1021/acs.jmedchem.0c00416/). Contradictory findings emerged regarding the role of hematopoietic cell kinase (HCK), where its genetic ablation was found to accelerate AD-like neuropathology, suggesting that microglial dysfunction may exacerbate neuroinflammation (ref: Lim doi.org/10.1007/s12035-020-01894-6/). Collectively, these studies underscore the intricate interplay between neuroinflammation and cytokine signaling in AD, highlighting potential therapeutic targets.

Therapeutic strategies targeting microglial function are gaining attention in Alzheimer's disease research. The protective PLCG2 variant has been associated with reduced tau pathology and cognitive decline, suggesting that enhancing microglial activity could be a viable therapeutic approach (ref: Kleineidam doi.org/10.1007/s00401-020-02138-6/). Additionally, the rhamnoside PL201 has been shown to significantly reduce activated microglia and proinflammatory cytokines in AD mouse models, indicating its potential as a neuroprotective agent (ref: An doi.org/10.3389/fimmu.2020.00162/). The study of LMP2 inhibitors has also revealed promising results, with compounds like YU102 improving cognitive impairments independently of amyloid deposits, suggesting a novel pathway for intervention (ref: Bhattarai doi.org/10.1021/acs.jmedchem.0c00416/). Furthermore, dihydroartemisinin has demonstrated the ability to ameliorate LPS-induced neuroinflammation by inhibiting the PI3K/AKT pathway, highlighting the potential of targeting specific signaling pathways in microglia (ref: Gao doi.org/10.1007/s11011-020-00533-2/). These findings collectively point towards a multifaceted approach to modulating microglial activity as a promising strategy in the treatment of Alzheimer's disease.

Genetic and molecular studies have provided significant insights into the mechanisms underlying Alzheimer's disease pathology. Research on rTg-DI rats has revealed robust neuroinflammation and perivascular pathology associated with cerebral amyloid angiopathy, a common comorbidity in AD, highlighting the role of microglial activation in disease progression (ref: Zhu doi.org/10.1186/s12974-020-01755-y/). Additionally, the genetic ablation of hematopoietic cell kinase (HCK) has been shown to accelerate AD-like neuropathology, suggesting that disruptions in microglial function can lead to increased amyloid-beta accumulation and cognitive decline (ref: Lim doi.org/10.1007/s12035-020-01894-6/). The study of TREM2 splicing in a humanized model of the R47H variant has also shed light on the genetic risk factors for AD, indicating that alterations in microglial signaling pathways may contribute to disease susceptibility (ref: Tambini doi.org/10.1038/s41598-020-60800-1/). Furthermore, the effects of amylin and pramlintide on amyloid processing have raised concerns about their potential role in increasing AD risk, emphasizing the need for careful evaluation of therapeutic agents (ref: Mousa doi.org/10.1038/s41598-020-60664-5/). These studies illustrate the complex interplay of genetic factors and molecular mechanisms in Alzheimer's disease, paving the way for targeted interventions.

Astrocytes and other glial cells play critical roles in the pathogenesis of Alzheimer's disease, particularly in response to neuroinflammation. A study examining the effects of early-life stress on astrocytes in APP/PS1 mice found that while astrocytic parameters were not significantly altered, the interplay between astrocytes and microglial responses to amyloid pathology was noteworthy (ref: Abbink doi.org/10.1186/s12974-020-01762-z/). This suggests that astrocytes may modulate the inflammatory environment in AD. Additionally, research on rTg-DI rats has shown that increased astrocyte activation accompanies neuroinflammation and amyloid pathology, indicating a potential role for astrocytes in the progression of cerebral amyloid angiopathy (ref: Zhu doi.org/10.1186/s12974-020-01755-y/). Furthermore, the glymphatic system's role in clearing nanoparticles from the brain has been linked to microglial function, revealing that impaired glymphatic clearance in AD models may exacerbate neuroinflammation (ref: Gu doi.org/10.1016/j.jconrel.2020.03.009/). Collectively, these findings highlight the importance of astrocytes and glial cells in modulating neuroinflammation and their potential as therapeutic targets in Alzheimer's disease.