Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer's Disease.
Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer's Disease.
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DOI：
10.1155/2012/685739
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发表时间：
2012
影响因子：
--
通讯作者：
Shimohama S
中科院分区：
文献类型：
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作者：
Takata K;Takada T;Ito A;Asai M;Tawa M;Saito Y;Ashihara E;Tomimoto H;Kitamura Y;Shimohama S
在阿尔茨海默病（AD）患者脑中，淀粉样蛋白-β（Aβ）肽的积累与活化的小胶质细胞相关。Aβ来源于淀粉样前体蛋白;存在两种主要形式的Aβ，即Aβ1-40（Aβ40）和Aβ1-42（Aβ42）。我们先前报道了大鼠小胶质细胞吞噬Aβ42和高迁移率族蛋白1（HMGB 1）（一种染色体蛋白）抑制吞噬作用。本研究观察了外源性HMGB 1对大鼠小胶质细胞Aβ40吞噬功能的影响。在外源性HMGB 1存在下，小胶质细胞胞浆中Aβ40显著增加，而细胞外Aβ40的减少被抑制。在此期间，HMGB 1与Aβ40共定位于细胞质中。此外，外源性HMGB 1可抑制大鼠小胶质细胞胞浆组分诱导的Aβ40降解。因此，细胞外HMGB 1可能与小胶质细胞胞质中的Aβ40一起内化，并抑制小胶质细胞对Aβ40的降解。这可能随后延迟Aβ40清除。我们进一步证实，在AD脑中，被活化的小胶质细胞包围的老年斑部分由Aβ40组成，细胞外HMGB 1沉积在这些斑块上。综上所述，小胶质细胞Aβ吞噬功能障碍可能是由HMGB 1在Aβ斑块上的细胞外积累引起的，并且其可能在AD的病理进展中起关键作用。
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.