A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.
A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.
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DOI：
10.1186/s13195-023-01330-6
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发表时间：
2023-10-19
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--
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载脂蛋白E基因型是散发性阿尔茨海默病（AD）的最大遗传危险因素。与APOE 3相比，APOE 4使AD风险增加12倍，这种影响在女性中更大。有证据表明，单向APOE可以通过神经炎症调节AD的风险和进展。事实上，APOE 4与AD患者和小鼠中较高的神经胶质活化和细胞因子水平相关。因此，确定有助于APOE 4相关神经炎症的途径是理解和治疗AD的重要方法。人体和体内证据表明，TLR 4，参与先天免疫系统的关键受体之一，可能参与APOE调节的神经炎症。与这一想法一致，我们先前证明TLR 4拮抗剂IAXO-101可以减少APOE 4胶质细胞培养物中LPS和Aβ诱导的细胞因子分泌。因此，本研究的目的是推进这些发现，并确定IAXO-101是否可以调节表达APOE 4的小鼠的神经炎症、Aβ病理学和行为。我们使用了表达5种家族性AD突变和人APOE 3（E3 FAD）或APOE 4（E4 FAD）的小鼠。雌性和雄性E4 FAD小鼠以及雌性E3 FAD小鼠在两种处理模式中用溶剂或IAO-101处理：从4至6月龄预防或从6至7月龄逆转。采用改良Morris水迷宫评价大鼠学习记忆能力。通过免疫组织化学评估Aβ沉积、纤维状淀粉样蛋白沉积、星形胶质细胞增生和小胶质细胞增生。采用ELISA法测定可溶性Aβ和apoE水平、不溶性apoE和Aβ水平以及IL-1β水平。在预防和逆转模式中，IAXO-101治疗导致雌性E4 FAD小鼠的Iba-1覆盖率降低，反应性小胶质细胞数量减少，记忆力改善。IAXO-101处理的雄性E4 FAD小鼠在RVS范例中也具有较低的Iba-1覆盖率和反应性，但对行为没有影响。IAXO-101处理对雌性E3 FAD小鼠的神经炎症和行为也没有影响。我们的数据支持TLR 4是调节APOE 4女性神经炎症和认知的潜在机制治疗靶点。在线版本包含补充材料，可通过10.1186/s13195-023-01330-6获得。
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. 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. 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. Our data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4 females. The online version contains supplementary material available at 10.1186/s13195-023-01330-6.
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影响因子：
3
作者：
Dela Justina V;Giachini FR;Sullivan JC;Webb RC
通讯作者：
Webb RC
影响因子：
5.3
作者：
Costa, Jessica;Martins, Solange;Cardoso, Ana L.
通讯作者：
Cardoso, Ana L.
影响因子：
15.1
作者：
Clayton K;Delpech JC;Herron S;Iwahara N;Ericsson M;Saito T;Saido TC;Ikezu S;Ikezu T
通讯作者：
Ikezu T
DOI：
10.1186/s13195-020-00712-4
发表时间：
2020-11-04
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Emrani S;Arain HA;DeMarshall C;Nuriel T
通讯作者：
Nuriel T
影响因子：
10.6
作者：
Guo L;Zhong MB;Zhang L;Zhang B;Cai D
通讯作者：
Cai D