Department of Experimental Medicine and Oncology, General Pathology Section, University of Torino, Torino, Italy.
J Alzheimers Dis. 2011;27(4):871-83. doi: 10.3233/JAD-2011-110884.
The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42, that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.
γ-分泌酶和β-分泌酶（BACE1）对淀粉样蛋白前体（AβPP）进行连续的内切酶切割，导致淀粉样蛋白-β（Aβ）的产生，其 C 端有两个变体，分别在残基 40 或残基 42。大脑组织中 Aβ42 的小、可溶性聚集物的积累是阿尔茨海默病（AD）的主要致病事件。然而，Aβ肽的生理活性仍然难以捉摸。在这里，我们表明 BACE1 的表达受 Aβ42 调节，通过 JNK/c-jun 信号通路增强 BACE1 基因转录。值得注意的是，Aβ40 对 BACE1 表达的影响要小得多。这些发现揭示了一个正反馈回路，其中 AβPP 的 γ-分泌酶切割释放出一种具有功能活性的肽 Aβ42，促进 BACE1 转录。因此，Aβ42 诱导的基因表达可能对 AD 中发生的神经元功能障碍和退化有影响。
