Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (6): 2454-2467.doi: 10.4103/NRR.NRR-D-24-01190

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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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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