4.8 Article

Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease

期刊

NEURON
卷 109, 期 2, 页码 257-+

出版社

CELL PRESS
DOI: 10.1016/j.neuron.2020.11.002

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资金

  1. National Institutes of Health (NIH)/National Institute on Aging [U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, R01AG068030]
  2. NIH/National Institute of Allergy and Infectious Diseases [U01AI111598]
  3. NIH/National Institute on Drug Abuse [R01DA043247]
  4. NIH/National Institute of Dental and Craniofacial Research [R03DE026814]
  5. NIH/National Institute of Diabetes and Digestive and Kidney Diseases [R01DK118243]
  6. Department of the Army [W81XWH-15-1-0706]
  7. Japan Society for the Promotion of Science KAKENHI [JP16K08637]
  8. Research Funding for Longevity Science from the National Center for Geriatrics and Gerontology, Japan [19-49, 19-7]

向作者/读者索取更多资源

This study identified neuronal gene subnetworks as the most dysregulated in late-onset Alzheimer's Disease, with ATP6V1A as a key regulator that can improve neuronal impairment caused by LOAD through a repositioned compound, NCH-51. The detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD provide a blueprint for developing next-generation therapeutic agents against the disease.
To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omits profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.

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