title: Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid β-peptide (Aβ), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major Aβ-degrading enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an (18) O-labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased Aβ levels and those induced by neprilysin deficiency independently of Aβ, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 (http://proteomecentral.proteomexchange.org/dataset/PXD000968 and (http://proteomecentral.proteomexchange.org/dataset/PXD001786). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels.
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.|Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.|Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Huddinge, Sweden.|Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Krishnapriya
authors.initials: K
authors.lastname: Loganathan
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Sekiguchi
authors.affiliation: Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Dept of Biotechnology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Tjernberg
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D015260:Neprilysin / Q000235:genetics*; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D011506:Proteins; D015260:Neprilysin
keywords: 18O-labeling; AD mouse model; Alzheimer's disease; Animal proteomics; Ingenuity Pathway Analysis; Neprilysin knockout mouse