Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease

Gao, Chao; Shen, Xianfeng; Tan, Yuyan; Chen, Shengdi

doi:10.1186/s12974-022-02580-1

Cited by 18 publications

(11 citation statements)

References 194 publications

(304 reference statements)

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“…Yan et al (2023) showed that Icariin treatment significantly reduced tau hyperphosphorylation at the Thr217, Ser199/202, Thr231, and Ser396/404 sites in AD mice. The pathophysiology of AD involves not only the accumulation of aberrant protein aggregates but also neuroinflammation ( Gao et al, 2022 ). Glial cells are the primary immune cells in the brain and exert beneficial and neuroprotective effects by removing pathogens.…”

Section: Resultsmentioning

confidence: 99%

HIF-1 signalling pathway was identified as a potential new pathway for Icariin’s treatment against Alzheimer’s disease based on preclinical evidence and bioinformatics

You

Yuan

et al. 2022

Front. Pharmacol.

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Aim: Alzheimer’s disease (AD) is a neurodegenerative condition that is characterized by the gradual loss of memory and cognitive function. Icariin, which is a natural chemical isolated from Epimedii herba, has been shown to protect against AD. This research examined the potential mechanisms of Icariin’s treatment against AD via a comprehensive review of relevant preclinical studies coupled with network pharmacology.Methods: The PubMed, Web of Science, CNKI, WANFANG, and VIP databases were used to identify the relevant studies. The pharmacological characteristics of Icariin were determined using the SwissADME and TCMSP databases. The overlapping targets of Icariin and AD were then utilized to conduct disease oncology (DO) analysis to identify possible hub targets of Icariin in the treatment of AD. The hub targets were then used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and the interactions of the targets and Icariin were assessed via molecular docking and molecular dynamics simulation (MDS).Results: According to the literature review, Icariin alleviates cognitive impairment by regulating the expression of Aβ1-42, Aβ1-40, BACE1, tau, hyperphosphorylated tau, and inflammatory mediators. DO analysis revealed 35 AD-related hub targets, and the HIF-1 signalling pathway was ranked first according to the KEGG pathway analysis. Icariin effectively docked with the 35 hub targets and HIF-1α, and the dynamic binding of the HIF-1-Icariin complex within 100 ns indicated that Icariin contributed to the stability of HIF-1α.Conclusion: In conclusion, our research used a literature review and network pharmacology methods to identify the HIF-1 signalling pathway as a potential pathway for Icariin’s treatment against AD.

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Section: Resultsmentioning

confidence: 99%

HIF-1 signalling pathway was identified as a potential new pathway for Icariin’s treatment against Alzheimer’s disease based on preclinical evidence and bioinformatics

You

Yuan

et al. 2022

Front. Pharmacol.

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“…However, considering the fact that we also included amyloid negative MCI cases in our study that might contain different underlying pathologies, future studies should confirm our results in larger MCI amyloid positive and negative groups. Furthermore, it could be interesting to further explore how a panel of these markers would be informative for monitoring the response of anti-inflammatory drugs [ 14 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease

Hok‐A‐Hin

Campo

Boiten

et al. 2023

J Neuroinflammation

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Background There is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer’s disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD. Methods We included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores. Results MIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB). Conclusion Inflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug–target engagement of inflammatory modulators.

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“…However, the role of microglia function in AD is complex and is dependent on many factors including activation state and disease stage. For example, it has been proposed that moderately activated microglia are neuroprotective in the early stages of AD, while chronically activated microglia may be detrimental in later stages (reviewed in [ 64 – 66 ]). Genetic AD risk factors and sex may also impact the extent that microglia are beneficial, neutral, or detrimental for cognitive function in AD.…”

Section: Discussionmentioning

confidence: 99%

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice

Balu,

Valencia-Olvera,

Nguyen

et al. 2023

Alz Res Therapy

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Background APOE genotype is the greatest genetic risk factor for sporadic Alzheimer’s disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in females. Evidence suggests that one-way APOE could modulate AD risk and progression through neuroinflammation. Indeed, APOE4 is associated with higher glial activation and cytokine levels in AD patients and mice. Therefore, identifying pathways that contribute to APOE4-associated neuroinflammation is an important approach for understanding and treating AD. Human and in vivo evidence suggests that TLR4, one of the key receptors involved in the innate immune system, could be involved in APOE-modulated neuroinflammation. Consistent with that idea, we previously demonstrated that the TLR4 antagonist IAXO-101 can reduce LPS- and Aβ-induced cytokine secretion in APOE4 glial cultures. Therefore, the goal of this study was to advance these findings and determine whether IAXO-101 can modulate neuroinflammation, Aβ pathology, and behavior in mice that express APOE4. Methods We used mice that express five familial AD mutations and human APOE3 (E3FAD) or APOE4 (E4FAD). Female and male E4FAD mice and female E3FAD mice were treated with vehicle or IAXO-101 in two treatment paradigms: prevention from 4 to 6 months of age or reversal from 6 to 7 months of age. Learning and memory were assessed by modified Morris water maze. Aβ deposition, fibrillar amyloid deposition, astrogliosis, and microgliosis were assessed by immunohistochemistry. Soluble levels of Aβ and apoE, insoluble levels of apoE and Aβ, and IL-1β were measured by ELISA. Results IAXO-101 treatment resulted in lower Iba-1 coverage, lower number of reactive microglia, and improved memory in female E4FAD mice in both prevention and reversal paradigms. IAXO-101-treated male E4FAD mice also had lower Iba-1 coverage and reactivity in the RVS paradigm, but there was no effect on behavior. There was also no effect of IAXO-101 treatment on neuroinflammation and behavior in female E3FAD mice. Conclusion Our data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4 females.

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Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease

Cited by 18 publications

References 194 publications

HIF-1 signalling pathway was identified as a potential new pathway for Icariin’s treatment against Alzheimer’s disease based on preclinical evidence and bioinformatics

HIF-1 signalling pathway was identified as a potential new pathway for Icariin’s treatment against Alzheimer’s disease based on preclinical evidence and bioinformatics

Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice

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