Multiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis
The molecular mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, remain poorly understood. Proteomics offers a crucial approach to elucidating AD pathogenesis, as alterations in protein expression are more directly linked to phenotypic outcomes than changes at the genetic or transcriptomic level. In this study, we develop multiscale proteomic network models for AD by integrating large-scale matched proteomic and genetic data from brain regions vulnerable to the disease. These models reveal detailed protein interaction structures and identify putative key driver proteins (KDPs) involved in AD progression. Notably, the network analysis uncovers an AD-associated subnetwork that captures glia-neuron interactions. AHNAK, a top KDP in this glia-neuron network, is experimentally validated in human induced pluripotent stem cell (iPSC)-based models of AD. This systematic identification of dysregulated protein regulatory networks and KDPs lays down a foundation for developing innovative therapeutic strategies for AD.
Authors
- Julia TCW (ORCID: https://orcid.org/0000-0002-3054-9374)
- Pavel Katsel (ORCID: https://orcid.org/0000-0001-8076-0162)
- Junmin Peng (ORCID: https://orcid.org/0000-0003-0472-7648)
- Dongming Cai (ORCID: https://orcid.org/0000-0002-0601-6826)
- Peng Xu (ORCID: https://orcid.org/0000-0001-8007-9879)
- Won‐Min Song (ORCID: https://orcid.org/0000-0003-0948-119X)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Erming Wang (ORCID: https://orcid.org/0009-0000-8056-0785)
- Erik C. B. Johnson (ORCID: https://orcid.org/0000-0002-0604-2944)
- Qian Lü (ORCID: https://orcid.org/0000-0001-7271-5804)
- Peyman Habibi (ORCID: https://orcid.org/0000-0002-6520-2768)
- Vahram H. Haroutunian (ORCID: https://orcid.org/0000-0001-5860-2512)
- Gongqi Yu (ORCID: https://orcid.org/0000-0001-7654-5232)
- Tony Tuck
- Kaiwen Yu (ORCID: https://orcid.org/0000-0002-6050-8477)
- Kristen Brennand (ORCID: https://orcid.org/0000-0003-0993-5956)
- Panos Roussos (ORCID: https://orcid.org/0000-0002-4640-6239)
- Yuxin Li (ORCID: https://orcid.org/0000-0001-9739-9860)
- Minghui Wang (ORCID: https://orcid.org/0000-0001-9171-4962)
- Qian Wang (ORCID: https://orcid.org/0000-0001-5504-0008)
- Bin Zhang (ORCID: https://orcid.org/0000-0002-1634-5703)
- Zhen Wang (ORCID: https://orcid.org/0000-0002-2725-8322)
- Xusheng Wang (ORCID: https://orcid.org/0000-0002-1759-9588)
- Aiqun Li (ORCID: https://orcid.org/0000-0003-1485-5352)
- Jia Geng (ORCID: https://orcid.org/0000-0001-8443-7231)
- Jiqing Cao
- David A. Bennett
- Nicholas T. Seyfried
- Li Zhu (ORCID: https://orcid.org/0009-0002-4905-3149)
Institutions
- Boston University (US)
- Rush University Medical Center (US)
- St. Jude Children's Research Hospital (US)
- Yale University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1016/j.cell.2025.08.038
- Citations
- 12
- Primary Topic
- Bioinformatics and Genomic Networks
- Type
- article
- Field-Weighted Citation Impact
- 9.67