Abstract：
:Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.
journal_name
Neuronjournal_title
Neuronauthors
Bai B,Wang X,Li Y,Chen PC,Yu K,Dey KK,Yarbro JM,Han X,Lutz BM,Rao S,Jiao Y,Sifford JM,Han J,Wang M,Tan H,Shaw TI,Cho JH,Zhou S,Wang H,Niu M,Mancieri A,Messler KA,Sun X,Wu Z,Pagala V,High AA,Bi W,Zhandoi
10.1016/j.neuron.2019.12.015subject
Has Abstractpub_date
2020-03-18 00:00:00pages
975-991.e7issue
6eissn
0896-6273issn
1097-4199pii
S0896-6273(19)31058-Xjournal_volume
105pub_type
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