The Cleavage Product of Amyloid-β Protein Precursor sAβPPα Modulates BAG3-Dependent Aggresome Formation and Enhances Cellular Proteasomal Activity
The Cleavage Product of Amyloid-β Protein Precursor sAβPPα Modulates BAG3-Dependent Aggresome Formation and Enhances Cellular Proteasomal Activity
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DOI：
10.3233/jad-140600
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发表时间：
2015-01-01
影响因子：
4
通讯作者：
Hajieva, Parvana
中科院分区：
文献类型：
--
作者：
Renziehausen, Jana;Hiebel, Christof;Hajieva, Parvana
阿尔茨海默病（Alzheimer's disease，AD）是一种以认知功能逐渐减退为特征的老年性痴呆。淀粉样β蛋白前体（A-PP）的异常裂解被认为在这种疾病的病理学中起重要作用。存在两种主要的A-PP加工途径：A-PP的淀粉样蛋白裂解导致产生可溶性N-末端片段sA β PP β，淀粉样蛋白-β（A β），其在AD脑中积累，以及A-PP胞内结构域（AICD）sA β PP α，p3和AICD在非淀粉样蛋白生成途径中产生。淀粉样蛋白生成与非淀粉样蛋白生成加工的流行导致sA β PP α耗竭和A β升高。虽然sA β PP α是一种被广泛接受的神经营养蛋白，但该片段的分子效应仍不清楚。不同的研究报道了AD脑中受损的蛋白质降解途径，指出蛋白酶体活性紊乱在这种疾病的发病机制中的作用。在这里，我们研究了sA β PP α在Bag 3介导的选择性大自噬和蛋白酶体降解中的可能作用。使用人IMR 90细胞、HEK 293细胞和原代神经元，我们证明sA β PP α在蛋白质和mRNA水平上阻止蛋白毒性应激诱导的Bag 3增加，表明转录调节。有趣的是，自噬的另外两个关键参与者p62和LC 3没有受到影响。此外，疾病相关蛋白聚集体的形成和积累显着减少sA β PP α。有趣的是，通过使用各种蛋白酶体底物证明，sA β PP α显著增加了蛋白酶体活性。我们的研究结果表明，sA β PP α调节Bag 3的表达，侵略形成，和蛋白酶体的活性，从而提供了第一个证据的功能sA β PP α的调节蛋白质。
Alzheimer's disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-beta protein precursor (A-PP) is thought to play an important role in the pathology of this disease. Two principal A-PP processing pathways exist: amyloidogenic cleavage of A-PP resulting in production of the soluble N-terminal fragment sA beta PP beta, amyloid-beta (A beta), which accumulates in AD brain, and the A-PP intracellular domain (AICD) sA beta PP alpha, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amyloidogenic processing leads to depletion of sA beta PP alpha and an increase in A beta. Although sA beta PP alpha is a well-accepted neurotrophic protein, molecular effects of this fragment remains unknown. Different studies reported impaired protein degradation pathways in AD brain, pointing to a role of disturbed proteasomal activity in the pathogenesis of this disease. Here we studied the possible role of sA beta PP alpha in Bag3-mediated selective macroautophagy and proteasomal degradation. Employing human IMR90 cells, HEK 293 cells, and primary neurons, we demonstrate that sA beta PP alpha prevents the proteotoxic stress-induced increase of Bag3 at the protein and at the mRNA level indicating a transcriptional regulation. Intriguingly, p62 and LC3, two other key players of autophagy, were not affected. Moreover, the formation and the accumulation of disease-related protein aggregates were significantly reduced by sA beta PP alpha. Interestingly, there was a significant increase of proteasomal activity by sA beta PP alpha as demonstrated by using various proteasome substrates. Our findings demonstrate that sA beta PP alpha modulates Bag3 expression, aggresome formation, and proteasomal activity, thereby providing first evidence for a function of sA beta PP alpha in the regulation of proteostasis.