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| Status |
Public on May 07, 2024 |
| Title |
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 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 across in vitro and in vivo models 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 the NPCmut mouse as a novel, short-lived in vivo model of AD characterized by accelerated brain aging, concluding that the NPCmut mouse model can serve as a potential short-lived in vivo model 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 diverse in vitro models. Considering the lack of an AD mouse model that recapitulates the physiological hallmarks of brain aging, the characterization of a short-lived NPC mouse model will further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of AD from a perspective of accelerated brain aging.
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| Overall design |
To identify novel biomarkers and treatment strategies against AD in the context of congenital disorders with increased AD-risk, we performed commonality analysis on AD and selected congenital disorders (DS, NPC, MPS I) human samples and mice samples from APP/PS1 mice and NPC1KO (NPC model) mice
We compared frontal cortex transcriptomic data from our NPC1KO mice to both APP/PS1 AD mouse frontal cortex transcriptomic data and human AD frontal cortex data
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| Contributor(s) |
Gujjala VA, Kaya A |
| Citation missing |
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| Submission date |
May 02, 2024 |
| Last update date |
May 07, 2024 |
| Contact name |
Vikas A Gujjala |
| E-mail(s) |
gujjalava@vcu.edu
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| Phone |
8049331404
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| Organization name |
Virginia Commonwealth University
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| Department |
Biology
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| Lab |
Kaya Lab
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| Street address |
1000 W Cary Street
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| City |
Richmond |
| State/province |
Virginia |
| ZIP/Postal code |
23284 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA1107268 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE266485_NPC1KO_FPKM_Counts.xlsx |
10.3 Mb |
(ftp)(http) |
XLSX |
| GSE266485_NPC1KO_Raw_Counts.xlsx |
7.6 Mb |
(ftp)(http) |
XLSX |
| GSE266485_NPC1_KO_F_FCvsWT_F_FC_deg.xls.gz |
4.5 Mb |
(ftp)(http) |
XLS |
| GSE266485_NPC1_KO_M_FCvsWT_M_FC_deg.xls.gz |
4.4 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
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