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针对下丘脑进行建模以研究与年龄相关的 DNA 甲基化，并开发针对男性小鼠模型中阿尔茨海默病样病理的 OXT-GnRH 联合治疗方法。

Targeting the hypothalamus for modeling age-related DNA methylation and developing OXT-GnRH combinational therapy against Alzheimer's disease-like pathologies in male mouse model.

机构信息

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.

出版信息

Nat Commun. 2024 Oct 31;15(1):9419. doi: 10.1038/s41467-024-53507-8.

DOI:10.1038/s41467-024-53507-8
PMID:39482312
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11528003/
Abstract

The hypothalamus plays an important role in aging, but it remains unclear regarding the underlying epigenetics and whether this hypothalamic basis can help address aging-related diseases. Here, by comparing mouse hypothalamus with two other limbic system components, we show that the hypothalamus is characterized by distinctively high-level DNA methylation during young age and by the distinct dynamics of DNA methylation and demethylation when approaching middle age. On the other hand, age-related DNA methylation in these limbic system components commonly and sensitively applies to genes in hypothalamic regulatory pathways, notably oxytocin (OXT) and gonadotropin-releasing hormone (GnRH) pathways. Middle age is associated with transcriptional declines of genes which encode OXT, GnRH and signaling components, which similarly occur in an Alzheimer's disease (AD)-like model. Therapeutically, OXT-GnRH combination is substantially more effective than individual peptides in treating AD-like disorders in male 5×FAD model. In conclusion, the hypothalamus is important for modeling age-related DNA methylation and developing hypothalamic strategies to combat AD.

摘要

下丘脑在衰老过程中起着重要作用，但关于其潜在的表观遗传学以及这种下丘脑基础是否有助于解决与衰老相关的疾病，目前仍不清楚。在这里，我们通过比较小鼠下丘脑与另外两个边缘系统成分，发现年轻时期下丘脑的 DNA 甲基化水平明显较高，而接近中年时 DNA 甲基化和去甲基化的动态变化也很明显。另一方面，这些边缘系统成分中的与年龄相关的 DNA 甲基化通常适用于下丘脑调节途径中的基因，特别是催产素 (OXT) 和促性腺激素释放激素 (GnRH) 途径。中年与编码 OXT、GnRH 和信号成分的基因的转录水平下降有关，这种情况也同样出现在阿尔茨海默病 (AD) 样模型中。在治疗方面，OXT-GnRH 联合治疗比单独使用肽类在治疗雄性 5×FAD 模型的 AD 样疾病方面更有效。总之，下丘脑对于模拟与年龄相关的 DNA 甲基化以及开发针对 AD 的下丘脑策略非常重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/5e164bf544e9/41467_2024_53507_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/e5eab0d76b6c/41467_2024_53507_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/686cce8e21a6/41467_2024_53507_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/9df260da02c6/41467_2024_53507_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/2973075b042b/41467_2024_53507_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/0ba7d54fb133/41467_2024_53507_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/7eb3991ed786/41467_2024_53507_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/205da2f7f3e1/41467_2024_53507_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/5e164bf544e9/41467_2024_53507_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/e5eab0d76b6c/41467_2024_53507_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/686cce8e21a6/41467_2024_53507_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/9df260da02c6/41467_2024_53507_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/2973075b042b/41467_2024_53507_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/0ba7d54fb133/41467_2024_53507_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/7eb3991ed786/41467_2024_53507_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/205da2f7f3e1/41467_2024_53507_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8272/11528003/5e164bf544e9/41467_2024_53507_Fig8_HTML.jpg

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