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: Kazuhiko Tagawa, Hidenori Homma, Ayumu Saito, Kyota Fujita, Xigui Chen, Seiya Imoto, Tsutomu Oka, Hikaru Ito, Kazumi Motoki, Chisato Yoshida, Hiroyuki Hatsuta, Shigeo Murayama, Takeshi Iwatsubo, Satoru Miyano, Hitoshi Okazawa
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 2 Pg. 540-58 (Jan 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25231903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amyloid beta-Peptides
• Intracellular Signaling Peptides and Proteins
• MARCKS protein, human
• Marcks protein, mouse
• Membrane Proteins
• Phosphoproteins
• Myristoylated Alanine-Rich C Kinase Substrate
• Protein Kinase C

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Brain (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Myristoylated Alanine-Rich C Kinase Substrate
• Phosphoproteins (genetics, metabolism)
• Phosphorylation
• Protein Kinase C (genetics, metabolism)
• Signal Transduction
• Synapses (metabolism)