Gujjala Vikas Anil, Abyadeh Morteza, Klimek Isaiah, Tyshkovskiy Alexander, Oz Naci, Castro José Pedro, Gladyshev Vadim N, Newton Jason, Kaya Alaattin
Department of Biology, Virginia Commonwealth University, Richmond, VA, USA.
Center for Integrative Life Sciences, Virginia Commonwealth University, Richmond, VA, USA.
Neural Regen Res. 2025 Apr 29. doi: 10.4103/NRR.NRR-D-24-01190.
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, Niemann- Pick 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.
阿尔茨海默病最初被认为是由与年龄相关的斑块积累引起的，近年来，研究越来越多地将阿尔茨海默病与溶酶体储存和代谢紊乱联系起来，其发病机制的解释已从淀粉样蛋白和tau蛋白积累转向氧化应激以及缺氧条件加剧的脂质和葡萄糖代谢受损。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明确。在此，我们应用疾病相似性方法，通过使用已知会增加阿尔茨海默病风险的先天性疾病（即唐氏综合征、尼曼-皮克C型病和黏多糖贮积症I型）的转录组数据来识别阿尔茨海默病的未知分子靶点。我们在这些疾病的体外和体内模型中发现了共同的通路、枢纽基因和微小RNA，作为神经保护和改善阿尔茨海默病病理的潜在分子靶点，其中许多靶点从未与阿尔茨海默病相关联。然后，我们通过将尼曼-皮克C型病小鼠模型的脑样本与阿尔茨海默病的人类和小鼠模型的脑样本并列比较，研究了其脑样本中的常见分子改变。详细的表型、分子、时间顺序和生物学衰老分析表明，Npc1tm(I1061T)Dso小鼠模型可作为脑衰老和阿尔茨海默病研究的潜在短寿命体内模型。这项研究代表了先天性疾病与神经退行性变关联的首次综合方法以及阿尔茨海默病研究的新视角，同时突出了各种体外模型中的缺点和缺乏相关性。考虑到缺乏能够概括脑衰老生理特征的阿尔茨海默病小鼠模型，短寿命的Npc1tm(I1061T)Dso小鼠模型可以进一步加速这些领域的研究，并从加速脑衰老的角度为理解阿尔茨海默病的分子机制提供独特模型。
