HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease

Sci Rep. 2016 Aug 25;6:31895. doi: 10.1038/srep31895.

Abstract

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, Aβ 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 Aβ 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 Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology
  • Disease Models, Animal
  • HMGB1 Protein / antagonists & inhibitors
  • HMGB1 Protein / metabolism*
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Targeted Therapy
  • Myristoylated Alanine-Rich C Kinase Substrate / chemistry
  • Myristoylated Alanine-Rich C Kinase Substrate / metabolism*
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurites / pathology*
  • Phosphorylation / drug effects
  • Serine / metabolism
  • Toll-Like Receptor 4 / metabolism*
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • HMGB1 Protein
  • HMGB1 protein, human
  • MAPT protein, human
  • MARCKS protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • tau Proteins
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Serine
  • Mitogen-Activated Protein Kinases