BRI2 ectodomain affects A beta(42) fibrillation and tau truncation in human neuroblastoma cells

作者：Del Campo M^*; Oliveira C R; Scheper W; Zwart R; Korth C; Mueller Schiffmann A; Kostallas G; Biverstal H; Presto J; Johansson J; Hoozemans J J; Pereira C F; Teunissen C E

来源：Cellular and Molecular Life Sciences, 2015, 72(8): 1599-1611.

DOI：10.1007/s00018-014-1769-y

• Alzheimer's disease
• ITM2b
• BRICHOS
• Aggregation
• Fibrillation
• Apoptosis

Alzheimer's disease (AD) is pathologically characterized by the presence of misfolded proteins such as amyloid beta (A beta) in senile plaques, and hyperphosphorylated tau and truncated tau in neurofibrillary tangles (NFT). The BRI2 protein inhibits A beta 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 A beta plaques and concomitant changes in its processing enzymes in early stages of AD. Here, we aimed to investigate the effects of recombinant BRI2 ectodomain (rBRI2(76-266)) on A beta 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 rBRI2(76-266) delays A beta fibril formation, although less efficiently than the BRI2 BRI-CHOS domain (BRI2 residues 113-231). In human neuroblastoma SH-SY5Y cells, rBRI2(76-266) 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. rBRI2(76-266) upregulated the chaperone BiP but did not modify the mRNA expression of other UPR markers (CHOP and Xbp-1). Strikingly, rBRI2(76-266) induced the activation of GSK3 beta but not the phosphorylation of tau. However, exposure to rBRI2(76-266) significantly induced the truncation of tau, indicating that BRI2 ectodomain can contribute to NFT formation. Since BRI2 can also regulate the metabolism of A beta, the current data suggests that BRI2 ectodomain is a potential nexus between A beta, tau pathology and neurodegeneration.

• 出版日期2015-4