Del Campo M, Oliveira C R, Scheper W, Zwart R, Korth C, Müller-Schiffmann A, Kostallas G, Biverstal H, Presto J, Johansson J, Hoozemans J J, Pereira C F, Teunissen C E
Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Center (VUmc), Room PK1 Br016, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands,
Cell Mol Life Sci. 2015 Apr;72(8):1599-611. doi: 10.1007/s00018-014-1769-y. Epub 2014 Oct 22.
Alzheimer's disease (AD) is pathologically characterized by the presence of misfolded proteins such as amyloid beta (Aβ) in senile plaques, and hyperphosphorylated tau and truncated tau in neurofibrillary tangles (NFT). The BRI2 protein inhibits Aβ aggregation via its BRICHOS domain and regulates critical proteins involved in initiating the amyloid cascade, which has been hypothesized to be central in AD pathogenesis. We recently detected the deposition of BRI2 ectodomain associated with Aβ plaques and concomitant changes in its processing enzymes in early stages of AD. Here, we aimed to investigate the effects of recombinant BRI2 ectodomain (rBRI276-266) on Aβ aggregation and on important molecular pathways involved in early stages of AD, including the unfolded protein response (UPR), phosphorylation and truncation of tau, as well as apoptosis. We found that rBRI276-266 delays Aβ fibril formation, although less efficiently than the BRI2 BRICHOS domain (BRI2 residues 113-231). In human neuroblastoma SH-SY5Y cells, rBRI276-266 slightly decreased cell viability and increased up to two-fold the Bax/Bcl-2 ratio and the subsequent activity of caspases 3 and 9, indicating activation of apoptosis. rBRI276-266 upregulated the chaperone BiP but did not modify the mRNA expression of other UPR markers (CHOP and Xbp-1). Strikingly, rBRI276-266 induced the activation of GSK3β but not the phosphorylation of tau. However, exposure to rBRI276-266 significantly induced the truncation of tau, indicating that BRI2 ectodomain can contribute to NFT formation. Since BRI2 can also regulate the metabolism of Aβ, the current data suggests that BRI2 ectodomain is a potential nexus between Aβ, tau pathology and neurodegeneration.
阿尔茨海默病（AD）的病理特征是在老年斑中存在错误折叠的蛋白质，如β淀粉样蛋白（Aβ），以及在神经原纤维缠结（NFT）中存在过度磷酸化的tau蛋白和截短的tau蛋白。BRI2蛋白通过其BRICHOS结构域抑制Aβ聚集，并调节参与启动淀粉样蛋白级联反应的关键蛋白，据推测该级联反应在AD发病机制中起核心作用。我们最近在AD早期检测到与Aβ斑块相关的BRI2胞外结构域沉积及其加工酶的伴随变化。在此，我们旨在研究重组BRI2胞外结构域（rBRI276 - 266）对Aβ聚集以及AD早期涉及的重要分子途径的影响，包括未折叠蛋白反应（UPR）、tau蛋白的磷酸化和截短以及细胞凋亡。我们发现rBRI276 - 266延迟了Aβ纤维的形成，尽管其效率低于BRI2的BRICHOS结构域（BRI2的113 - 231位氨基酸残基）。在人神经母细胞瘤SH - SY5Y细胞中，rBRI276 - 266轻微降低细胞活力，并使Bax/Bcl - 2比值增加至两倍，随后增加半胱天冬酶3和9的活性，表明细胞凋亡被激活。rBRI276 - 266上调伴侣蛋白BiP，但未改变其他UPR标志物（CHOP和Xbp - 1）的mRNA表达。令人惊讶的是，rBRI276 - 266诱导了糖原合酶激酶3β（GSK3β）的激活，但未诱导tau蛋白的磷酸化。然而，暴露于rBRI276 - 266显著诱导了tau蛋白的截短，表明BRI2胞外结构域可导致NFT的形成。由于BRI2还可以调节Aβ的代谢，目前的数据表明BRI2胞外结构域是Aβ、tau病理和神经退行性变之间的潜在联系。
