ArticleAlzheimer's research & therapy2023
A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.
Article in Alzheimer's research & therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 30 citations in OpenAlex.
- Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer's disease.Inflammopharmacology · 2026Review
- microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer's disease patients.Acta neuropathologica communications · 2026Article
- Taking its TOLL: the role of toll-like receptor 4 in human health and disease, and its potential as a therapeutic target.Frontiers in immunology · 2026Review
- Direct toll-like receptor 4 inhibition in Alzheimer's disease models: a focused scoping review of inflammatory, amyloid-handling, and functional outcomes.Frontiers in aging neuroscience · 2026Review
- Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease.Translational neurodegeneration · 2025Review
- Sex-specific changes in energy demand during the preplaque stage in a transgenic Alzheimer's mouse model.Biology of sex differences · 2025Article
- The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review.Brain sciences · 2025Review
- Mechanistic Role of Astrocytic Rac1 Protein in Alzheimer's Disease.Aging and disease · 2025Review
- Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer's Disease with Therapeutic Implications.International journal of molecular sciences · 2025Review
- Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer's Disease.Cells · 2025Review
- Stem Cells as a Novel Source for Regenerative Medicinal Applications in Alzheimer's Disease: An Update.Current molecular medicine · 2025Review
- Microglial activation states and their implications for Alzheimer's Disease.The journal of prevention of Alzheimer's disease · 2025Review
- Estradiol improves behavior in FAD transgenic mice that expressFrontiers in endocrinology · 2024Article
- A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3.Alzheimer's research & therapy · 2023Article
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundAPOE 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.
methodsWe 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.
resultsIAXO-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.
conclusionOur data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4 females.
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