Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.
Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.
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DOI：
10.1016/j.ebiom.2017.08.028
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发表时间：
2017-10
期刊：
影响因子：
11.1
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Raven F;Ward JF;Zoltowska KM;Wan Y;Bylykbashi E;Miller SJ;Shen X;Choi SH;Rynearson KD;Berezovska O;Wagner SL;Tanzi RE;Zhang C
阿尔茨海默病（AD）的一个中心致病事件是Aβ42肽的积累，Aβ42肽由淀粉样蛋白-β前体蛋白（APP）通过β-和γ-分泌酶裂解产生。我们开发了一类可溶性2-氨基噻唑γ-分泌酶调节剂（SGSM），优先降低Aβ42水平。然而，SGSM在AD动物和表达家族性AD突变的细胞中的作用以及γ-分泌酶调节的机制在很大程度上仍然未知。在这里，使用表达FAD突变的动物和细胞研究了这种SGSM支架的代表SGSM-36。SGSM-36优先降低Aβ42水平，而不影响APP的α-和β-分泌酶加工，也不影响Notch加工。此外，使用基于细胞的荧光寿命成像显微镜分析，在γ-分泌酶复合物内鉴定了允许SGSM-36进入的变构位点。总的来说，这些研究提供了关于这类SGSM的机制见解，并加强了它们在AD中的治疗潜力。一类新的可溶性2-氨基噻唑γ-分泌酶调节剂（SGSMs）被表征为AD的潜在治疗剂。使用AD动物和细胞模型，代表性化合物SGSM-36优先降低Aβ42水平。在γ-分泌酶内鉴定出SGSM-36可接近的变构位点。阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，目前没有治疗方法来减缓或停止疾病进展。大量证据表明，Aβ42肽的产生和积累是导致AD的主要病理过程。我们开发了一类可溶性2-氨基噻唑γ-分泌酶调节剂（SGSM），优先降低Aβ42水平。目前的研究已初步阐明了我们的SGSM降低Aβ42水平和减轻β-淀粉样蛋白病理的机制。这些实验的结果将是有用的，对正在进行的努力，对开发一种有效的治疗和预防AD的疗法。
A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD. A novel class soluble 2-aminothiazole γ-secretase modulators (SGSMs) are characterized as potential therapeutics for AD. A representative compound, SGSM-36, preferentially decreases Aβ42 levels using animal and cell models of AD. An allosteric site was identified within γ-secretase to be accessible by SGSM-36. Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there is currently no treatment to slow or halt disease progression. Considerable evidence shows that the primary pathological event leading to AD is the production and accumulation of Aβ42 peptide. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. The presented studies have primarily elucidated the mechanisms by which our SGSMs decrease Aβ42 levels and attenuate β-amyloid pathology. The results of these experiments will be useful toward the ongoing efforts toward the development of an effective therapy for the treatment and prevention of AD.
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影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
5.4
作者：
Kuzuya A;Zoltowska KM;Post KL;Arimon M;Li X;Svirsky S;Maesako M;Muzikansky A;Gautam V;Kovacs D;Hyman BT;Berezovska O
通讯作者：
Berezovska O
DOI：
10.1523/jneurosci.2775-12.2012
发表时间：
2012-11-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lauritzen I;Pardossi-Piquard R;Bauer C;Brigham E;Abraham JD;Ranaldi S;Fraser P;St-George-Hyslop P;Le Thuc O;Espin V;Chami L;Dunys J;Checler F
通讯作者：
Checler F
影响因子：
4.8
作者：
Burton, Catherine R.;Meredith, Jere E.;Toyn, Jeremy H.
通讯作者：
Toyn, Jeremy H.
影响因子：
11
作者：
Brendel, M.;Jaworska, A.;Rominger, A.
通讯作者：
Rominger, A.