Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment.

Autor:	Dammer EB; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA., Shantaraman A; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Ping L; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Duong DM; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA., Gerasimov ES; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Ravindran SP; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Gudmundsdottir V; Icelandic Heart Association, 201 Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland., Frick EA; Icelandic Heart Association, 201 Kopavogur, Iceland., Gomez GT; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Walker KA; Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA., Emilsson V; Icelandic Heart Association, 201 Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland., Jennings LL; Novartis Biomedical Research, Cambridge, MA 02139, USA., Gudnason V; Icelandic Heart Association, 201 Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland., Western D; Department of Psychiatry, Washington University, St. Louis, MO 63108, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO 63108, USA., Cruchaga C; Department of Psychiatry, Washington University, St. Louis, MO 63108, USA.; NeuroGenomics and Informatics, Washington University, St. Louis, MO 63108, USA., Lah JJ; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Wingo TS; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Wingo AP; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA.; Division of Mental Health, Atlanta VA Medical Center, Decatur, GA 30033, USA., Seyfried NT; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Levey AI; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Johnson ECB; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2024 Jun 26; Vol. 16 (753), pp. eadn3504. Date of Electronic Publication: 2024 Jun 26.
DOI:	10.1126/scitranslmed.adn3504
Abstrakt:	Alzheimer's disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies-tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module-the network module most strongly correlated to cognitive function-were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau.
Databáze:	MEDLINE
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