Heat Shock Cognate 70 Inhibitor, VER-155008, Reduces Memory Deficits and Axonal Degeneration in a Mouse Model of Alzheimer's Disease.
Heat Shock Cognate 70 Inhibitor, VER-155008, Reduces Memory Deficits and Axonal Degeneration in a Mouse Model of Alzheimer's Disease.
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DOI：
10.3389/fphar.2018.00048
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发表时间：
2018
影响因子：
5.6
通讯作者：
Tohda C
中科院分区：
文献类型：
--
作者：
Yang X;Tohda C
阿尔茨海默病（AD）是一种进行性神经退行性疾病，导致大脑结构改变和记忆障碍。我们假设重建神经网络对AD患者的记忆恢复至关重要。热休克同源蛋白70 （HSC70）是热休克蛋白分子伴侣家族的一员，在阿尔茨海默病患者的大脑中表达上调，最近的研究表明HSC70促进阿尔茨海默病患者轴突变性和病理进展。然而，HSC70抑制对轴突发育和记忆功能的直接影响尚未被研究。在这项研究中，我们研究了一种小分子HSC70抑制剂VER-155008对AD小鼠模型（5XFAD小鼠）轴突形态和记忆功能的影响。我们发现VER-155008在体外显著促进淀粉样蛋白β处理神经元的轴突再生，并改善5XFAD小鼠的物体识别、定位和情景样记忆。此外，经腹腔给药后，VER-155008进入大脑，表明VER-155008在大脑中原位起作用。免疫组化结果显示，VER-155008减少了5XFAD小鼠鼻周皮层淀粉样斑块和CA1的球泡样轴突肿胀，表明VER-155008在体内也逆转了轴突变性。此外，在5XFAD小鼠中，给药VER-155008减少了AD的两个主要病理特征，即淀粉样斑块和成对的螺旋丝tau积聚。这是第一个表明抑制HSC70功能可能对轴突再生和ad样症状逆转至关重要的报告。我们的研究提供了证据，证明HSC70可以作为阿尔茨海默病治疗的新靶点。
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in structural brain changes and memory impairment. We hypothesized that reconstructing neural networks is essential for memory recovery in AD. Heat shock cognate 70 (HSC70), a member of the heat shock protein family of molecular chaperones, is upregulated in AD patient brains, and recent studies have demonstrated that HSC70 facilitates axonal degeneration and pathological progression in AD. However, the direct effects of HSC70 inhibition on axonal development and memory function have never been investigated. In this study, we examined the effects of a small-molecule HSC70 inhibitor, VER-155008, on axonal morphology and memory function in a mouse model of AD (5XFAD mice). We found that VER-155008 significantly promoted axonal regrowth in amyloid β-treated neurons in vitro and improved object recognition, location, and episodic-like memory in 5XFAD mice. Furthermore, VER-155008 penetrated into the brain after intraperitoneal administration, suggesting that VER-155008 acts in the brain in situ. Immunohistochemistry revealed that VER-155008 reduced bulb-like axonal swelling in the amyloid plaques in the perirhinal cortex and CA1 in 5XFAD mice, indicating that VER-155008 also reverses axonal degeneration in vivo. Moreover, the two main pathological features of AD, amyloid plaques and paired helical filament tau accumulation, were reduced by VER-155008 administration in 5XFAD mice. This is the first report to show that the inhibition of HSC70 function may be critical for axonal regeneration and AD-like symptom reversal. Our study provides evidence that HSC70 can be used as a new therapeutic target for AD treatment.
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影响因子：
3.7
作者：
Schlecht R;Scholz SR;Dahmen H;Wegener A;Sirrenberg C;Musil D;Bomke J;Eggenweiler HM;Mayer MP;Bukau B
通讯作者：
Bukau B
影响因子：
4.2
作者：
Durairajan, Siva Sundara Kumar;Liu, Liang-Feng;Li, Min
通讯作者：
Li, Min
影响因子：
5.3
作者：
Christensen, MA;Zhou, WH;Song, WH
通讯作者：
Song, WH
影响因子：
7.3
作者：
Tohda, C.;Tamura, T.;Komatsu, K.
通讯作者：
Komatsu, K.
影响因子：
4.6
作者：
Tohda, Chihiro;Urano, Takuya;Umezaki, Masahito;Nemere, Ilka;Kuboyama, Tomoharu
通讯作者：
Kuboyama, Tomoharu