A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer’s disease and aging research
Abstract Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer’s disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD 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 AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs acrossin vitroandin vivomodels of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed NPCmutmouse as a novel, short-livedin vivomodel of AD characterized by accelerated brain aging, concluding that NPCmutmouse model can serve as a potential short-livedin vivomodel for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diversein vitromodels. Our findings provide a foundation for future animal and clinical studies and will lead to a better understanding of the molecular mechanisms underpinning the observed association between neurological congenital diseases and AD, thus has the potential to accelerate diagnostic and therapeutic applications against common types of dementia..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 26. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gujjala, Vikas Anil [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.04.19.590328 |
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| PPN (Katalog-ID): |
XBI043382215 |
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| 245 | 1 | 0 | |a A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer’s disease and aging research |
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| 520 | |a Abstract Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer’s disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD 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 AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs acrossin vitroandin vivomodels of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed NPCmutmouse as a novel, short-livedin vivomodel of AD characterized by accelerated brain aging, concluding that NPCmutmouse model can serve as a potential short-livedin vivomodel for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diversein vitromodels. Our findings provide a foundation for future animal and clinical studies and will lead to a better understanding of the molecular mechanisms underpinning the observed association between neurological congenital diseases and AD, thus has the potential to accelerate diagnostic and therapeutic applications against common types of dementia. | ||
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| 700 | 1 | |a Newton, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Kaya, Alaattin |e verfasserin |4 aut | |
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