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International Journal of Alzheimer’s Disease
Volume 2012 (2012), Article ID 685739, 11 pages
Research Article

Microglial Amyloid- 𝜷 1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer’s Disease

1Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
2Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
3Department of Neurology, Mie University, Graduate School of Medicine, Tsu 514-8507, Japan
4Department of Neurology, School of Medicine, Sapporo Medical University, S1W16, Chuo-ku, Sapporo 060-8543, Japan

Received 30 November 2011; Accepted 24 February 2012

Academic Editor: Akio Suzumura

Copyright © 2012 Kazuyuki Takata et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


In Alzheimer disease (AD) patient brains, the accumulation of amyloid- 𝛽 (A 𝛽 ) peptides is associated with activated microglia. A 𝛽 is derived from the amyloid precursor protein; two major forms of A 𝛽 , that is, A 𝛽 1-40 (A 𝛽 40) and A 𝛽 1-42 (A 𝛽 42), exist. We previously reported that rat microglia phagocytose A 𝛽 42, and high mobility group box protein 1 (HMGB1), a chromosomal protein, inhibits phagocytosis. In the present study, we investigated the effects of exogenous HMGB1 on rat microglial A 𝛽 40 phagocytosis. In the presence of exogenous HMGB1, A 𝛽 40 markedly increased in microglial cytoplasm, and the reduction of extracellular A 𝛽 40 was inhibited. During this period, HMGB1 was colocalized with A 𝛽 40 in the cytoplasm. Furthermore, exogenous HMGB1 inhibited the degradation of A 𝛽 40 induced by the rat microglial cytosolic fraction. Thus, extracellular HMGB1 may internalize with A 𝛽 40 in the microglial cytoplasm and inhibit A 𝛽 40 degradation by microglia. This may subsequently delay A 𝛽 40 clearance. We further confirmed that in AD brains, the parts of senile plaques surrounded by activated microglia are composed of A 𝛽 40, and extracellular HMGB1 is deposited on these plaques. Taken together, microglial A 𝛽 phagocytosis dysfunction may be caused by HMGB1 that accumulates extracellularly on A 𝛽 plaques, and it may be critically involved in the pathological progression of AD.