Neuner Sarah M, Garfinkel Benjamin P, Wilmott Lynda A, Ignatowska-Jankowska Bogna M, Citri Ami, Orly Joseph, Lu Lu, Overall Rupert W, Mulligan Megan K, Kempermann Gerd, Williams Robert W, O'Connell Kristen M S, Kaczorowski Catherine C
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Neurobiol Aging. 2016 Oct;46:58-67. doi: 10.1016/j.neurobiolaging.2016.06.008. Epub 2016 Jun 17.
An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.
个体的基因构成在决定对认知衰老的易感性方面起着重要作用。识别导致认知衰老的特定基因可能有助于对高危患者进行早期诊断，以及确定治疗或预防症状发展的新治疗靶点。在人类研究中识别这些特定基因面临的挑战包括复杂的遗传学、难以控制环境因素以及获取人类脑组织的机会有限。在此，我们使用基因多样化的小鼠群体将Hp1bp3鉴定为认知衰老的一种新型调节因子，并证实与认知功能正常的对照组相比，认知受损老年人海马体中HP1BP3蛋白水平显著降低。在小鼠中删除功能性Hp1bp3会重现老年受损小鼠和人类的记忆缺陷特征，进一步支持了Hp1bp3和相关分子网络是认知衰老调节因子的观点。总体而言，我们的结果表明Hp1bp3可能作为对抗认知衰老的潜在靶点，并证明了基因多样化动物模型在研究复杂人类疾病中的实用性。
