Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer's disease.
Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer's disease.
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DOI：
10.1186/s13195-016-0199-5
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Koenig G
中科院分区：
文献类型：
--
作者：
Blain JF;Bursavich MG;Freeman EA;Hrdlicka LA;Hodgdon HE;Chen T;Costa DE;Harrison BA;Kapadnis S;Murphy DA;Nolan S;Tu Z;Tang C;Burnett DA;Patzke H;Koenig G
家族性阿尔茨海默病（FAD）是由淀粉样前体蛋白（APP）或早老素（PS）突变引起的。大多数PS突变（占FAD病例的大多数）导致淀粉样β（Aβ）肽的较长形式与较短形式的比例增加。γ-分泌酶调节剂（GSM）用于阿尔茨海默病的治疗原理是基于这种遗传证据以及显示γ-分泌酶复合物的持续合成能力变化的酶动力学测量。这项分析表明，GSM可能会抵消PS突变对APP加工的一些影响，从而解决早发性FAD的根本原因。不幸的是，该领域已经产生了很少的，如果有的话，具有良好的中枢神经系统（CNS）药物样特性的分子，使机制的研究证据。我们使用多种细胞测定表征了新型GSM FRM-36143，以确定其体外效力和脱靶活性以及其逆转PS突变效应的潜力。我们还在野生型小鼠和大鼠体内测试了其功效。与已发表的GSM相比，FRM-36143具有显著改善的CNS药物样特性。在H4细胞中，其对Aβ42的体外EC 50为35 nM，可将大鼠脑脊液中的Aβ42降低至基线的58%，还可增加非淀粉样蛋白生成肽Aβ37和Aβ38。它不抑制Notch加工，也不抑制24-脱氢胆固醇还原酶（DHCR 24）活性。最有趣的是，它可以逆转早老素突变对体外APP加工的影响。FRM-36143在Aβ调节方面具有GSM的所有特征。由于FRM-36143能够逆转PS突变的影响，我们建议靶向具有这种遗传缺陷的患者将是在临床上测试GSM疗效的最佳方法。虽然淀粉样蛋白假说仍在用β位点APP裂解酶抑制剂和单克隆抗体在散发性AD中进行测试，但我们认为这不是FAD的假说。由于GSM可以纠正PS突变引起的分子缺陷，因此当在疾病过程中足够早地治疗时，它们有希望为患者提供益处。
Familial Alzheimer’s disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aβ) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer’s disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex. This analysis suggests that GSMs could potentially offset some of the effects of PS mutations on APP processing, thereby addressing the root cause of early onset FAD. Unfortunately, the field has generated few, if any, molecules with good central nervous system (CNS) drug-like properties to enable proof-of-mechanism studies. We characterized the novel GSM FRM-36143 using multiple cellular assays to determine its in vitro potency and off-target activity as well as its potential to reverse the effect of PS mutations. We also tested its efficacy in vivo in wild-type mice and rats. FRM-36143 has much improved CNS drug-like properties compared to published GSMs. It has an in vitro EC50 for Aβ42 of 35 nM in H4 cells, can reduce Aβ42 to 58 % of the baseline in rat cerebrospinal fluid, and also increases the non-amyloidogenic peptides Aβ37 and Aβ38. It does not inhibit Notch processing, nor does it inhibit 24-dehydrocholesterol reductase (DHCR24) activity. Most interestingly, it can reverse the effects of presenilin mutations on APP processing in vitro. FRM-36143 possesses all the characteristics of a GSM in terms of Aβ modulation Because FRM-36143 was able to reverse the effect of PS mutations, we suggest that targeting patients with this genetic defect would be the best approach at testing the efficacy of a GSM in the clinic. While the amyloid hypothesis is still being tested with β-site APP-cleaving enzyme inhibitors and monoclonal antibodies in sporadic AD, we believe it is not a hypothesis for FAD. Since GSMs can correct the molecular defect caused by PS mutations, they have the promise to provide benefits to the patients when treated early enough in the course of the disease.
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影响因子：
2.9
作者：
Funamoto, S;Morshima-Kawashima, M;Ihara, Y
通讯作者：
Ihara, Y
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
3.7
作者：
Mattsson N;Rajendran L;Zetterberg H;Gustavsson M;Andreasson U;Olsson M;Brinkmalm G;Lundkvist J;Jacobson LH;Perrot L;Neumann U;Borghys H;Mercken M;Dhuyvetter D;Jeppsson F;Blennow K;Portelius E
通讯作者：
Portelius E
影响因子：
7.3
作者：
Bursavich, Matthew G.;Harrison, Bryce A.;Blain, Jean-Francois
通讯作者：
Blain, Jean-Francois