Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer’s Disease

Kazuyuki Takata,Hidekazu Tomimoto,Manami Tawa,Mayo Asai,Eishi Ashihara,Shun Shimohama,Aina Ito,Yoshihisa Kitamura,Yuki Saito,Tetsuya Takada

doi:10.1155/2012/685739

Abstract

In Alzheimer disease (AD) patient brains, the accumulation of amyloid-β (Aβ) peptides is associated with activated microglia. Aβ is derived from the amyloid precursor protein; two major forms of Aβ, that is, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), exist. We previously reported that rat microglia phagocytose Aβ42, 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 Aβ40 phagocytosis. In the presence of exogenous HMGB1, Aβ40 markedly increased in microglial cytoplasm, and the reduction of extracellular Aβ40 was inhibited. During this period, HMGB1 was colocalized with Aβ40 in the cytoplasm. Furthermore, exogenous HMGB1 inhibited the degradation of Aβ40 induced by the rat microglial cytosolic fraction. Thus, extracellular HMGB1 may internalize with Aβ40 in the microglial cytoplasm and inhibit Aβ40 degradation by microglia. This may subsequently delay Aβ40 clearance. We further confirmed that in AD brains, the parts of senile plaques surrounded by activated microglia are composed of Aβ40, and extracellular HMGB1 is deposited on these plaques. Taken together, microglial Aβ phagocytosis dysfunction may be caused by HMGB1 that accumulates extracellularly on Aβ plaques, and it may be critically involved in the pathological progression of AD.

Highlights

Alzheimer’s disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, accumulation of neurofibrillary tangles (NFTs), and loss of synapses and neurons in particular brain areas [1]
Microglia were transferred to 24-well plates (3.0 × 105 cells/well) and were allowed to adhere at 37◦C overnight; they were treated with sterilized phosphatebuffered saline (PBS) as the vehicle or synthetic human Aβs (Aβ40 or Aβ42; Anaspec, San Jose, CA) in the presence or absence of calf thymus-purified high mobility group box protein 1 (HMGB1) (WAKO Chemicals, Osaka, Japan)
We examined the effect of exogenous HMGB1 on the Aβ40 degradation induced by the microglial cytosolic fraction (Figure 4(b))

Summary

Introduction

Alzheimer’s disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, accumulation of neurofibrillary tangles (NFTs), and loss of synapses and neurons in particular brain areas [1]. Experimental studies using transgenic AD mouse models have demonstrated that Aβ accelerates NFT formation [2, 3] and is closely associated with synaptic damage [4]. Aβ reduction in the brain by Aβ immunization restores cognitive functions in transgenic AD mouse models [5,6,7,8,9] and appears to slow cognitive decline in human AD patients [10]. Among the variations in Aβ, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42) are the major species found in AD brains.

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