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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

Author

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  • Salman Sadullah Usmani

    (Albert Einstein College of Medicine)

  • Hyun-Gug Jung

    (Albert Einstein College of Medicine)

  • Qichao Zhang

    (Albert Einstein College of Medicine)

  • Min Woo Kim

    (Albert Einstein College of Medicine)

  • Yuna Choi

    (Albert Einstein College of Medicine)

  • Ahmet Burak Caglayan

    (Albert Einstein College of Medicine)

  • Dongsheng Cai

    (Albert Einstein College of Medicine)

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.

Suggested Citation

  • Salman Sadullah Usmani & Hyun-Gug Jung & Qichao Zhang & Min Woo Kim & Yuna Choi & Ahmet Burak Caglayan & Dongsheng Cai, 2024. "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," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53507-8
    DOI: 10.1038/s41467-024-53507-8
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    References listed on IDEAS

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    1. Sara Zocher & Rupert W. Overall & Mathias Lesche & Andreas Dahl & Gerd Kempermann, 2021. "Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Henriette van Praag & Alejandro F. Schinder & Brian R. Christie & Nicolas Toni & Theo D. Palmer & Fred H. Gage, 2002. "Functional neurogenesis in the adult hippocampus," Nature, Nature, vol. 415(6875), pages 1030-1034, February.
    3. Guo Zhang & Juxue Li & Sudarshana Purkayastha & Yizhe Tang & Hai Zhang & Ye Yin & Bo Li & Gang Liu & Dongsheng Cai, 2013. "Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH," Nature, Nature, vol. 497(7448), pages 211-216, May.
    4. Yalin Zhang & Min Soo Kim & Baosen Jia & Jingqi Yan & Juan Pablo Zuniga-Hertz & Cheng Han & Dongsheng Cai, 2017. "Hypothalamic stem cells control ageing speed partly through exosomal miRNAs," Nature, Nature, vol. 548(7665), pages 52-57, August.
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