Neuron
Volume 109, Issue 2, 20 January 2021, Pages 257-272.e14
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Article
Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer’s Disease

https://doi.org/10.1016/j.neuron.2020.11.002Get rights and content
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Highlights

  • Development of gene network models of four cortical areas affected by LOAD

  • Identification of region-specific molecular changes and gene subnetworks in LOAD

  • ATP6V1A is a top key regulator of a neuronal subnetwork most disrupted in LOAD

  • NCH-51 normalizes neuronal impairment and neurodegeneration caused by ATP6V1A deficit

Summary

To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of multi-omics 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.

Keywords

Alzheimer’s disease
omics
network biology
neuronal dysregulation
ATP6V1A
human induced pluripotent stem cell
NGN2 neurons
Drosophila
NCH-51

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These authors contributed equally

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