Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease
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SUMMARY: To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A , a critical subunit of vacuolar-type H + -ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.
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The PHG is most vulnerable in AD as manifested by marked transcriptomic dysregulation.
“The results are consistent with previous DEG analyses (19) of the MSBB-AD transcriptomic data and suggest that the PHG is most vulnerable in AD as manifested by marked transcriptomic dysregulation.”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [19]
A particular candidate compound identified using molecular signature data alone using an in silico drug repositioning algorithm was able to increase the expression level of ATP6V1A and restore long-term potentiation and memory formation in both cultured neurons and AD mouse models.
“For instance, a particular candidate compound identified using molecular signature data alone using an in silico drug repositioning algorithm (47) was able to increase the expression level of ATP6V1A and restore long-term potentiation and memory formation in both cultured neurons and AD mouse models (19).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [19]
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- Authors
- Wang, M., Li, A., Sekiya, M., Beckmann, N. D., Quan, X., Schrode, N., Fernando, M. B., Yu, A., Zhu, L., Cao, J., Lyu, L., Horgusluoglu, E., Wang, Q., Guo, L., Wang, Y.-S., Neff, R., Song, W.-M., Wang, E., Shen, Q., Zhou, X., Ming, C., Ho, S.-M., Vatansever, S., Kaniskan, H. U., Jin, J., Zhou, M.-M., Ando, K., Ho, L., Slesinger, P. A., Yue, Z., Zhu, J., Gandy, S., Ehrlich, M. E., Cai, D., Haroutunian, V., Iijima, K. M., Schadt, E., Brennand, K. J., & Zhang, B.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Nagoya City University (JP)
- National Center for Geriatrics and Gerontology (JP)
- James J. Peters VA Medical Center (US)
- Tisch Cancer Institute (US)
- Tokyo Metropolitan University (JP)
- Corresponding author
- Zhang, Bin
- ORCID
- Wang, Minghui
- Li, Aiqun
- Sekiya, Michiko
- Beckmann, Noam D.
- Schrode, Nadine
- Fernando, Michael B.
- Zhu, Li
- Lyu, Liwei
- Horgusluoglu, Emrin
- Wang, Qian
- Guo, Lei
- Neff, Ryan
- Song, Won-min
- Wang, Erming
- Zhou, Xianxiao
- Ho, Seok-Man
- Vatansever, Sezen
- Jin, Jian
- Zhou, Ming-Ming
- Ando, Kanae
- Ho, Lap
- Slesinger, Paul A.
- Yue, Zhenyu
- Zhu, Jun
- Gandy, Sam
- Ehrlich, Michelle E.
- Cai, Dongming
- Haroutunian, Vahram
- Iijima, Koichi M.
- Brennand, Kristen J.
- Zhang, Bin
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2019-10-01
- OpenAlex
- W2977611708
- Cited by
- 6
- References
- 11
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health (W81XWH)
- Japan Society for the Promotion of Science (16K08637)
- National Institute on Aging (U01AG058635, R01AG057907, U01AG046170, RF1AG054014, RF1AG057440, R01AG062355, U01AG052411)
- National Institute of Allergy and Infectious Diseases (U01AI111598)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118243)
- National Institute of Dental and Craniofacial Research (R03DE026814)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- late-onset Alzheimer's disease, molecular networks, ATP6V1A, vacuolar H+-ATPase, parahippocampal gyrus, cortical gene expression, disease severity, therapeutic target, human induced pluripotent stem cell-derived neurons, Drosophila model
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