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.
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PKC is one of the key kinases activated in AD.
“Studies have shown that PKC is one of the key kinases activated in AD, and PKC substrates make up over half of the core molecules in AD. 75 , 76”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [76]
PKC substrates make up over half of the core molecules in AD.
“Studies have shown that PKC is one of the key kinases activated in AD, and PKC substrates make up over half of the core molecules in AD. 75 , 76”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [76]
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Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes
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- Authors
- Tagawa, K., Homma, H., Saito, A., Fujita, K., Chen, X., Imoto, S., Oka, T., Ito, H., Motoki, K., Yoshida, C., Hatsuta, H., Murayama, S., Iwatsubo, T., Miyano, S., & Okazawa, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- The University of Tokyo (JP)
- Corresponding author
- Okazawa, Hitoshi
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-09-17
- Volume
- 24
- Issue
- 2
- Pages
- 540-558
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2141240737
- Cited by
- 86
- References
- 9
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 1 · 2023: 12 · 2022: 13 · 2021: 12 · 2020: 4 · 2019: 1 · 2018: 13 · 2017: 6 · 2016: 9 · 2015: 3
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Tokyo Medical and Dental University
- Foundation of Synapse and Neurocircuit Pathology
- Japan Society for the Promotion of Science (22110002, 24500378)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, preclinical Alzheimer's disease, phosphoproteome, amyloid-beta deposition, MARCKS, protein phosphorylation, protein-protein interaction network, protein kinase C, calcium/calmodulin-dependent protein kinase, kinase inhibition, AD mouse model, postmortem brain
- MeSH terms
- Myristoylated Alanine-Rich C Kinase Substrate, Alzheimer Disease, Animals, Brain, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Phosphoproteins, Phosphorylation, Protein Kinase C, Synapses, Signal Transduction, Amyloid beta-Peptides, Intracellular Signaling Peptides and Proteins, Mice
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