Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition
Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition
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DOI：
10.1073/pnas.0908953107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Jiang, Ying;Mullaney, Kerry A.;Nixon, Ralph A.
β-淀粉样前体蛋白（APP）基因的额外拷贝导致21三体（DS）中的早发性阿尔茨海默病（AD）。内体功能障碍在DS和AD中发展得非常早，并且与神经变性的机制有关。在这里，我们表明，从个人与DS成纤维细胞的形态和功能的内吞异常逆转降低APP或β-APP裂解酶1（BACE-1）的表达，使用短发夹RNA结构。相比之下，在正常二体（2N）成纤维细胞中，可以通过过表达APP或由BACE-1（β CTF）产生的C-末端APP片段来诱导内体病理学，所有这些都提高了β CTF的水平。不能进行β-切割的APP突变形式的表达对内体没有影响。APP γ-分泌酶的药理学抑制显著降低A β产生但提高β CTF水平，也诱导2N成纤维细胞中的AD样内体功能障碍，并使DS成纤维细胞中的这种病理学恶化。这些发现强烈暗示APP和APP的β CTF，并排除A β和α CTF作为DS和AD中内吞途径功能障碍的原因，强调了BACE-1抑制在AD治疗中的潜在多方面价值。
An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (beta CTF), all of which elevate the levels of beta CTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced A beta production but raised beta CTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the beta CTF of APP, and exclude A beta and the alpha CTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.