Paradoxical effect of TrkA inhibition in Alzheimer's disease models.
Paradoxical effect of TrkA inhibition in Alzheimer's disease models.
复制标题
DOI：
10.3233/jad-130017
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Bredesen DE
中科院分区：
文献类型：
--
作者：
Zhang Q;Descamps O;Hart MJ;Poksay KS;Spilman P;Kane DJ;Gorostiza O;John V;Bredesen DE
对阻断淀粉样β蛋白前体（AβPP）半胱天冬酶裂解的化合物进行无偏筛选，鉴定出ADDN-1351，其使AβPP-C31降低90%。靶点鉴定研究表明，ADDN-1351是一种TrkA抑制剂，在补充研究中，TrkA过表达增加了AβPP-C31和细胞死亡。TrkA与AβPP相互作用，抑制Aβ PP介导的转录激活。此外，用已知的TrkA抑制剂GW 441756处理PDAPP转基因小鼠增加了sAβPPα和sAβPPα与Aβ的比率。这些结果表明，TrkA抑制，而不是神经生长因子激活作为一种新的治疗方法，并提出了这样的方法可能会抵消过度活跃的信号传导导致的活性NGF-TrkA复合物的积累，由于减少逆行运输。结果还表明，阿尔茨海默病最佳治疗的一个组成部分可能是TrkA抑制剂。
An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ ratio. These results suggest TrkA inhibition—rather than NGF activation—as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer’s disease may be a TrkA inhibitor.