期刊
CELL REPORTS
卷 31, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.107807
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资金
- National Institute of Neurological Disorders and Stroke (NINDS), United States [R25NS065723, P30NS055077]
- National Institute on Aging (NIA), United States [R01AG053960, R01AG057911, R01AG061800, RF1AG057470, RF1AG05747101, U01AG046161, P50AG025688]
- Emory University [NIA U01 AG046161, NIA P50 AG025688, NIA P30 NS055077]
- National Institute of Neurological Disorders and Stroke [U24 NS072026]
- National Institute on Aging [P30 AG19610]
- Arizona Department of Health Services, United States [211002]
- Arizona Biomedical Research Commission, United States [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research, United States
- NIA [P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949]
- NINDS [R01 NS080820]
- CurePSP Foundation, United States
- Mayo Foundation, United States
Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership - Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority of, but not all, modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in mitogen-activated protein kinase (MAPK) signaling. Genetic risk enriches in modules changing early in disease and indicates that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high-confidence proteomic changes enriched in genetic risk represent targets for drug discovery.
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