@article{b80ca915d4144d2f8dd5f00aa416e5b8,
title = "Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease",
abstract = "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 = "ATP6V1A, Alzheimer's disease, Drosophila, NCH-51, NGN2 neurons, human induced pluripotent stem cell, network biology, neuronal dysregulation, omics",
author = "Minghui Wang and Aiqun Li and Michiko Sekiya and Beckmann, {Noam D.} and Xiuming Quan and Nadine Schrode and Fernando, {Michael B.} and Alex Yu and Li Zhu and Jiqing Cao and Liwei Lyu and Emrin Horgusluoglu and Qian Wang and Lei Guo and Wang, {Yuan shuo} and Ryan Neff and Song, {Won min} and Erming Wang and Qi Shen and Xianxiao Zhou and Chen Ming and Ho, {Seok Man} and Sezen Vatansever and Kaniskan, {H. {\"U}mit} and Jian Jin and Zhou, {Ming Ming} and Kanae Ando and Lap Ho and Slesinger, {Paul A.} and Zhenyu Yue and Jun Zhu and Pavel Katsel and Sam Gandy and Ehrlich, {Michelle E.} and Valentina Fossati and Scott Noggle and Dongming Cai and Vahram Haroutunian and Iijima, {Koichi M.} and Eric Schadt and Brennand, {Kristen J.} and Bin Zhang",
note = "Funding Information: We thank Ni-ka Ford and Dr. Gale Justin from the Instructional Technology Group at the Icahn School of Medicine at Mount Sinai for producing the illustration of Graphical Abstract and Figure 1. We thank the Bloomington Drosophila Stock Center and the Vienna Drosophila Resource Center for fly stocks. We thank Mette Peters and Nicole Kauer for setting up the data sharing page on the Synapse platform. This work was supported in part by the computational and data resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. This work was supported in part by grants from the National Institutes of Health (NIH)/National Institute on Aging (U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, and R01AG068030), NIH/National Institute of Allergy and Infectious Diseases (U01AI111598), NIH/National Institute on Drug Abuse (R01DA043247), NIH/National Institute of Dental and Craniofacial Research (R03DE026814), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118243), Department of the Army (W81XWH-15-1-0706), Japan Society for the Promotion of Science KAKENHI (JP16K08637 to K.I.), and Research Funding for Longevity Science from the National Center for Geriatrics and Gerontology, Japan (grants 19-49 to M.S. and 19-7 to K.I.). Conceptualization, B.Z. and E.S.; Investigation, M.W. A.L. M.S. N.D.B. and X.Q.; Formal Analysis, M.W. A.L. N.S. and M.S.; Data Curation, V.H. P.K. M.W. E.W. R.N. Y.-S.W. W.-M.S. Q.S. X.Z. L.G. C.M. E.H. and S.V.; Software, Y.-S.W. and J.Z.; Resources, V.H. V.F. S.N. S.G. and M.E.E.; Validation, L.L. A.Y. M.B.F. P.A.S. S.-M.H. L.Z. J.C. Q.W. H.{\"U}.K. J.J. M.-M.Z. K.A. D.C. and Z.Y.; Writing – Original Draft, M.W. A.L. M.S. K.M.I. K.J.B. and B.Z.; Writing – Review & Editing, all authors; Visualization, M.W. A.L. A.Y. and M.S.; Supervision, B.Z. K.J.B. and K.M.I.; Project Administration, B.Z.; Funding Acquisition, B.Z. The authors declare no competing interests. Funding Information: We thank Ni-ka Ford and Dr. Gale Justin from the Instructional Technology Group at the Icahn School of Medicine at Mount Sinai for producing the illustration of Graphical Abstract and Figure 1 . We thank the Bloomington Drosophila Stock Center and the Vienna Drosophila Resource Center for fly stocks. We thank Mette Peters and Nicole Kauer for setting up the data sharing page on the Synapse platform. This work was supported in part by the computational and data resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. This work was supported in part by grants from the National Institutes of Health (NIH)/National Institute on Aging (U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, and R01AG068030), NIH /National Institute of Allergy and Infectious Diseases (U01AI111598), NIH /National Institute on Drug Abuse (R01DA043247), NIH /National Institute of Dental and Craniofacial Research (R03DE026814), NIH /National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118243), Department of the Army ( W81XWH-15-1-0706 ), Japan Society for the Promotion of Science KAKENHI ( JP16K08637 to K.I.), and Research Funding for Longevity Science from the National Center for Geriatrics and Gerontology , Japan (grants 19-49 to M.S. and 19-7 to K.I.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
day = "20",
doi = "10.1016/j.neuron.2020.11.002",
language = "English",
volume = "109",
pages = "257--272.e14",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}