Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep31895
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Funding
- Brain Mapping by Integrated Neurotechnologies for Disease Studies from Japan agency for Medical research and Development (AMED)
- Strategic Research Program for Brain Sciences (SRPBS) from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Foundation of Synapse and Neurocircuit Pathology
- Grants-in-Aid for Scientific Research [26290019, 16K07040, 16H02655] Funding Source: KAKEN
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Alzheimer's disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, A beta and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of A beta and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases, and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of A beta plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and A beta mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by A beta-dependent and A beta-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with A beta and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.
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