High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity.
One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. According to the amyloid hypothesis, the increase or accumulation of amyloid-beta (Abeta) peptides in the brain parenchyma is the primary event that influences AD pathology. Although the role of microglia in AD pathology has not been clarified, their involvement in Abeta clearance has been noted. High mobility group box protein-1 (HMGB1) is an abundant nonhistone chromosomal protein. We reported recently that HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. In this study, diffuse HMGB1 immunoreactivity was observed around dying neurons in the kainic acid- and Abeta1-42 (Abeta42)-injected rat hippocampi. HMGB1 also colocalized with Abeta in the Abeta42-injected rats but not in transgenic mice, which show massive Abeta production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Abeta42 and accelerated neurodegeneration in Abeta42-injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Abeta42 clearance and enhance the neurotoxicity of Abeta42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD.
Takata
Kazuyuki
K
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Kitamura
Yoshihisa
Y
Tsuchiya
Daiju
D
Kawasaki
Toshiyuki
T
Taniguchi
Takashi
T
Shimohama
Shun
S
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000502:physiology*; D016923:Cell Death; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000502:physiology*
D016229:Amyloid beta-Peptides; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D007608:Kainic Acid