title: Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain.
abstract: Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models and human AD postmortem brains. We identified commonly changed phosphoproteins in multiple models and also determined phosphoproteins related to initiation of amyloid beta (Aβ) deposition in the mouse brain. After confirming these proteins were also changed in and human AD brains, we put the proteins on experimentally verified protein-protein interaction databases. Surprisingly, most of the core phosphoproteins were directly connected, and they formed a functional network linked to synaptic spine formation. The change of the core network started at a preclinical stage even before histological Aβ deposition. Systems biology analyses suggested that phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) by overactivated kinases including protein kinases C and calmodulin-dependent kinases initiates synapse pathology. Two-photon microscopic observation revealed recovery of abnormal spine formation in the AD model mice by targeting a core protein MARCKS or by inhibiting candidate kinases, supporting our hypothesis formulated based on phosphoproteome analysis.
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Homma
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Xigui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Motoki
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Yoshida
authors.affiliation: Department of Neuropathology, Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Department of Neuropathology, Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan and.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan okazawa-tky@umin.ac.jp okazawa.npat@mri.tmd.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C