Suppression of Alzheimer's Disease-Related Phenotypes by Expression of Heat Shock Protein 70 in Mice
Suppression of Alzheimer's Disease-Related Phenotypes by Expression of Heat Shock Protein 70 in Mice
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DOI：
10.1523/jneurosci.5478-10.2011
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发表时间：
2011-04-06
影响因子：
5.3
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Hoshino, Tatsuya;Murao, Naoya;Mizushima, Tohru
淀粉样β肽（A β）在阿尔茨海默病（AD）的发病机制中起重要作用。A β通过β-淀粉样前体蛋白（APP）的蛋白水解产生，并通过酶介导的降解和小胶质细胞和星形胶质细胞的吞噬作用清除。一些细胞因子，如TGF-β 1，刺激这种吞噬作用。相反，HSP 70表达的细胞上调提供了针对A β的细胞保护。还报道了与抑制A β寡聚化和刺激A β吞噬作用有关的HSP 70活性。虽然这些体外结果表明，刺激HSP 70的表达可以证明有效治疗AD，但缺乏体内证据支持这一观点。在这项研究中，我们解决这个问题，使用转基因小鼠表达HSP 70和/或突变形式的APP（APPsw）。表达APPsw的转基因小鼠在与表达HSP 70的转基因小鼠杂交时表现出较少的明显认知缺陷。表达HSP 70的转基因小鼠也显示出较低水平的A β，A β斑块沉积，神经元和突触损失比对照小鼠。免疫印迹实验和β-和γ-分泌酶活性的直接测量表明，HSP 70的过表达不影响A β的产生。相反，HSP 70过表达确实导致A β降解酶和TGF-β 1在体内和体外的表达上调。这些结果表明，HSP 70在小鼠中的过表达不仅抑制AD的病理而且抑制AD的功能表型。这项研究提供了第一个体内证据，证实了HSP 70对预防或治疗AD的潜在治疗益处。
Amyloid-beta peptide (A beta) plays an important role in the pathogenesis of Alzheimer's disease (AD). A beta is generated by proteolysis of beta-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-beta 1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against A beta. HSP70 activity in relation to inhibition of A beta oligomerization and stimulation of A beta phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of A beta, A beta plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of beta- and gamma-secretase activity suggested that overexpression of HSP70 does not affect the production A beta. In contrast, HSP70 overexpression did lead to upregulation of the expression of A beta-degrading enzyme and TGF-beta 1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.