Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.
Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.
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DOI：
10.1016/j.nbd.2014.08.017
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发表时间：
2015-02
影响因子：
6.1
通讯作者：
Lashuel, Hilal A.
中科院分区：
文献类型：
--
作者：
Eleuteri, Simona;Di Giovanni, Saviana;Rockenstein, Edward;Mante, Mike;Adame, Antony;Trejo, Margarita;Wrasidlo, Wolf;Wu, Fang;Fraering, Patrick C.;Masliah, Eliezer;Lashuel, Hilal A.
关键词：
Aβ蓄积在阿尔茨海默病（Alzheimer's disease，AD）的发病机制中起着重要作用。近年来的研究表明，Aβ成核聚合过程是Aβ纤维形成、病理扩散和毒性的关键。因此，靶向该过程代表了减缓或阻断疾病进展的有效治疗策略。为了发现可能干扰Aβ接种能力、毒性和病理扩散的化合物，我们使用接种聚合试验在体外筛选了FDA批准的药物集中库，并鉴定了特异性干扰Aβ接种介导的原纤维生长和毒性的小分子抑制剂。发现米托蒽醌、连硫堇和六氯酚是原纤维生长的最强抑制剂，并保护原代皮层神经元培养物免受Aβ诱导的毒性。接下来，我们评估了这三种抑制剂在AD mThy 1-APPtg小鼠模型（8月龄小鼠）中的体内作用。我们发现，米托蒽醌和双硫堇，而不是六氯酚，稳定弥漫性淀粉样斑块，降低Aβ42寡聚体的水平，改善突触丢失，神经元损伤和星形胶质细胞增生。总之，我们的研究结果表明，靶向纤维生长和Aβ播种能力构成了预防AD神经变性和疾病进展的可行且有效的策略。
Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represent an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.
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DOI：
10.1523/jneurosci.3088-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Langer F;Eisele YS;Fritschi SK;Staufenbiel M;Walker LC;Jucker M
通讯作者：
Jucker M
影响因子：
2.9
作者：
Lee SJ;Lim HS;Masliah E;Lee HJ
通讯作者：
Lee HJ
影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
2.9
作者：
Colombo, Raffaella;Carofti, Angelo;De Lorenzi, Ersilia
通讯作者：
De Lorenzi, Ersilia
影响因子：
3.5
作者：
Kraszpulski, M;Soininen, H;Alafuzoff, I
通讯作者：
Alafuzoff, I