The impact of mild episodic ketosis on microglia and hippocampal long-term depression in 5xFAD mice

IF 2.5 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY FASEB bioAdvances Pub Date : 2024-10-23 DOI:10.1096/fba.2024-00123
Jacopo Di Lucente, Jon J. Ramsey, Lee-Way Jin, Izumi Maezawa
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Abstract

Ketotherapeutics is a potential metabolic intervention for mitigating dementias; however, its mechanisms and optimal methods of application are not well understood. Our previous in vitro study showed that β-hydroxybutyrate (BHB), a major ketone body, reverses pathological features of amyloid-β oligomer (AβO)-activated microglia. Here we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer's disease (AD) mouse model. A short 1-week regimen of daily intraperitoneal injection of BHB (250 mg/kg), which induced brief and mild daily episodic ketosis, was sufficient to mitigate pro-inflammatory microglia activation and reduce brain amyloid-β deposition by enhancing phagocytosis. Remarkably, it mitigated the deficits of hippocampal long-term depression but not long-term potentiation, and this effect was linked to suppression of NLRP3 inflammasome-generated IL-1β. As ketogenic diets are known for poor compliance, our study opens the possibility for alternative approaches such as short-term BHB injections or dietary ketone esters that are less restrictive, potentially safer, and easier for compliance.

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轻度发作性酮症对5xFAD小鼠小胶质细胞和海马长期抑郁的影响。
酮疗法是缓解痴呆的潜在代谢干预;然而,其作用机理和最佳应用方法尚不清楚。我们之前的体外研究表明,β-羟基丁酸酯(BHB)是一种主要的酮体,可以逆转淀粉样蛋白-β寡聚物(a β o)激活的小胶质细胞的病理特征。我们在5xFAD阿尔茨海默病(AD)小鼠模型中测试了BHB对小胶质细胞和突触可塑性的体内影响。每天腹腔注射BHB (250 mg/kg) 1周的短期方案,可诱导短暂和轻度的每日发作性酮症,足以减轻促炎小胶质细胞的激活,并通过增强吞噬作用减少脑淀粉样蛋白-β沉积。值得注意的是,它减轻了海马长期抑郁的缺陷,但没有长期增强,这种效果与抑制NLRP3炎症小体产生的IL-1β有关。由于生酮饮食的依从性较差,我们的研究开辟了替代方法的可能性,例如短期注射BHB或饮食酮酯,这些方法限制较少,可能更安全,更容易依从性。
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来源期刊
FASEB bioAdvances
FASEB bioAdvances Multiple-
CiteScore
5.40
自引率
3.70%
发文量
56
审稿时长
10 weeks
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