APOEε4基因型对中年大鼠海马神经发生和祖细胞的性别特异性影响

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Bonnie H Lee, Melike Cevizci, Stephanie E Lieblich, Liisa A M Galea
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引用次数: 0

摘要

背景:阿尔茨海默病(Alzheimer's disease, AD)对女性的影响尤为严重,而载脂蛋白(APOE) ε4等位基因的存在进一步加剧了这些性别差异,载脂蛋白(APOE) ε4等位基因是迟发性AD的首要遗传危险因素。为了进一步了解迟发性阿尔茨海默病风险对男性和女性的不同影响,本研究探讨了APOEε4如何影响中年大鼠海马神经发生和小胶质细胞,这是阿尔茨海默病发病机制中关键的神经可塑性标志物。方法:建立表达人源化(h) APOEε4等位基因的大鼠模型,检测13月龄雄性和雌性大鼠海马齿状回成体神经发生(神经祖细胞和新生神经元)和免疫细胞(小胶质细胞)的标志物。结果:我们观察到中年神经发生的基本性别差异,野生型雄性大鼠齿状回神经祖细胞和新生神经元密度高于野生型雌性大鼠。与野生型雄性大鼠相比,hAPOEε4雄性大鼠表现出较少的神经祖细胞、较少的新生神经元和较多的小胶质细胞。另一方面,雌性hAPOEε4大鼠比雌性野生型大鼠表现出更多的新生神经元。有趣的是,无论基因型如何,女性都比男性有更多的小胶质细胞。进行相关性研究是为了进一步阐明这些生物标志物之间的性别差异。值得注意的是,神经祖细胞与新生神经元之间存在显著正相关,新生神经元与小胶质细胞之间存在显著负相关,但仅在雄性大鼠中存在。结论:与hAPOEε4危险因子对雄性海马神经发生影响的明确模式不同,雌性海马神经祖细胞水平不变,新生神经元密度增加。此外,神经发生和小胶质细胞之间的关系在男性中显著相关,而在女性中则没有。这表明女性可能在中年时对hapoe4基因型表现出代偿性反应。总的来说,这些结果说明了彻底检查性别对阿尔茨海默病内表型影响的重要性,因为它可能揭示与阿尔茨海默病相关的性别特异性途径和保护机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats.

Background: Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats.

Methods: A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats.

Results: We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats.

Conclusion: In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.

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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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