Age-dependent sex differences in cofilin1 pathway (LIMK1/SSH1) and its association with AD biomarkers after chronic systemic inflammation in mice

IF 3.7 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging Pub Date : 2024-09-07 DOI:10.1016/j.neurobiolaging.2024.09.003

Amsha S. Alsegiani, Zahoor A. Shah

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引用次数: 0

Abstract

Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. Cofilin1 is a stress protein that activates microglia and induces neuroinflammation, but its role in CSI at different aging stages remains unidentified. Therefore, the study aims to identify cofilin1 and its upstream regulators LIMK1 and SSH1 after CSI in young-, middle-, and advanced-aged mice. CSI was induced by injecting the male and female mice with a sub-lethal dose of Lipopolysaccharide weekly for six weeks. The results showed that normal male mice did not show cofilin pathway dysregulation, but a significant dysregulation was observed in CSI advanced-aged mice. In females, cofilin1 dysregulation was observed in healthy and CSI advanced-aged mice, while significant cofilin1 dysregulation was observed in middle-aged mice during CSI. Furthermore, cofilin1 pathway dysregulations correlated with Alzheimer's disease (AD) biomarkers in the brain and saliva, astrocyte activation, synaptic degeneration, neurobehavioral impairments, gut-microbiota abnormalities, and circulatory inflammation. These results provide new insights into cofilin1 sex and age-dependent mechanistic differences that might help identify targets for modulating neuroinflammation and early onset of AD.

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小鼠慢性系统性炎症后，cofilin1通路（LIMK1/SSH1）的年龄依赖性性别差异及其与AD生物标志物的关系

慢性全身性炎症（CSI）会导致神经炎症和神经退行性变。Cofilin1是一种应激蛋白，可激活小胶质细胞并诱导神经炎症，但它在不同衰老阶段的CSI中的作用仍未确定。因此，本研究旨在确定cofilin1及其上游调节因子LIMK1和SSH1在幼、中、高龄小鼠CSI后的作用。研究人员每周给雌雄小鼠注射亚致死剂量的脂多糖，连续六周诱导小鼠发生CSI。结果显示，正常雄性小鼠没有出现cofilin通路失调，但在CSI高龄小鼠中观察到明显的失调。在雌性小鼠中，健康小鼠和CSI高龄小鼠都观察到了cofilin1的失调，而在CSI期间的中年小鼠中则观察到了明显的cofilin1失调。此外，cofilin1通路失调与大脑和唾液中的阿尔茨海默病（AD）生物标志物、星形胶质细胞活化、突触变性、神经行为障碍、肠道微生物群异常和循环系统炎症相关。这些结果提供了有关 cofilin1 性别和年龄依赖性机理差异的新见解，可能有助于确定调节神经炎症和 AD 早期发病的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurobiology of Aging 医学-老年医学

CiteScore

8.40

自引率

2.40%

发文量

225

审稿时长

67 days

期刊介绍： Neurobiology of Aging publishes the results of studies in behavior, biochemistry, cell biology, endocrinology, molecular biology, morphology, neurology, neuropathology, pharmacology, physiology and protein chemistry in which the primary emphasis involves mechanisms of nervous system changes with age or diseases associated with age. Reviews and primary research articles are included, occasionally accompanied by open peer commentary. Letters to the Editor and brief communications are also acceptable. Brief reports of highly time-sensitive material are usually treated as rapid communications in which case editorial review is completed within six weeks and publication scheduled for the next available issue.