中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2454-2467.doi: 10.4103/NRR.NRR-D-24-01190

• 原著:退行性病与再生 • 上一篇    下一篇

加速大脑衰老的 C 型尼曼-皮克短寿小鼠作为阿尔茨海默病研究的新型模型

  

  • 出版日期:2026-06-15 发布日期:2025-09-19

Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

Vikas Anil Gujjala1, 2, 3, Morteza Abyadeh1, 3, Isaiah Klimek1 , Alexander Tyshkovskiy4 , Naci Oz1, 2, 3, José Pedro Castro5, 6, Vadim N. Gladyshev4 , Jason Newton1, 2, *, Alaattin Kaya1, 2, 3, *   

  1. 1 Department of Biology, Virginia Commonwealth University, Richmond, VA, USA;  2 Center for Integrative Life Sciences, Virginia Commonwealth University, Richmond, VA, USA;  3 Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA;  4 Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;  5 i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;  6 Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
  • Online:2026-06-15 Published:2025-09-19
  • Contact: Jason Newton, PhD, newtonjc2@vcu.edu; Alaattin Kaya, PhD, qcc6zm@virginia.edu.
  • Supported by:
    This study was supported by the NIA/NIH (1K01AG060040). Studies performed by JN were funded by the NICHD/NIH (5R00HD096117); Microscopy Core Facility supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.

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摘要：

阿尔茨海默病（AD）最初被认为是由与年龄相关的斑块累积引起的，近年来，越来越多的研究将阿尔茨海默病与溶酶体贮存和代谢紊乱联系起来，对其发病机制的解释也从淀粉样蛋白和tau累积转向氧化应激以及缺氧条件下加重的脂质和葡萄糖代谢障碍。然而，将这些细胞过程和条件与疾病进展联系起来的潜在机制尚未确定。实验采用了一种疾病相似性方法，通过使用已知会增加注意力缺失症风险的先天性疾病（即唐氏综合征（DS）、尼曼皮克病 C 型（NPC）和粘多糖病 I 型（MPS I））的转录组数据来识别注意力缺失症的未知分子靶标。实验在这些疾病的体外和体内模型中发现了共同的通路、枢纽基因和 miRNA，它们是神经保护和改善注意力缺失症病理的潜在分子靶点，其中许多从未与注意力缺失症相关。然后，将鼻咽癌疾病小鼠模型的脑样本与人类和小鼠注意力缺失症模型的脑样本并列，研究了鼻咽癌疾病小鼠模型脑样本中常见的分子改变。详细的表型、分子、年代学和生物衰老分析表明，Npc1tm(I1061T)Dso小鼠模型可作为一种潜在的短期体内脑衰老和AD研究模型。这项研究全面探讨了先天性疾病与神经退行性病变的关系，为AD研究提供了新的视角，同时也凸显了各种体外模型的不足之处和缺乏相关性。考虑到目前缺乏能再现脑衰老生理特征的AD小鼠模型，短寿命的Npc1tm（I1061T）Dso小鼠模型能进一步加速这些领域的研究，并为从加速脑衰老的角度理解AD的分子机制提供了一个独特的模型。

https://orcid.org/0000-0003-2952-2008 (Jason Newton); https://orcid.org/0000-0002-6132-5197 (Alaattin Kaya)

关键词: 衰老生物标志物, 阿尔茨海默病, 比较基因组学, 先天性疾病, 唐氏综合征, 小鼠模型, 粘多糖I型, 尼曼皮克病C型

Abstract: Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk, namely Down syndrome, NiemannPick type C disease, and mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology, many of which have never been associated with Alzheimer’s disease. We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease. Detailed phenotypic, molecular, chronological, and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging, the short-lived Npc1tm(I1061T)Dso mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.

Key words: aging biomarkers, Alzheimer’s disease, comparative genomics, congenital diseases, Down syndrome, mouse model, mucopolysaccharidoses I, Niemann-Pick type C disease