title: Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer's disease.
abstract: AβpE3-42 (N-terminal truncated amyloid-β peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AβpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes.
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Yang
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Wittnam
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D025341:Principal Component Analysis; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D010446:Peptide Fragments; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-; D013973:Thyrotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases