TITLE

BRI2 ectodomain affects Aβ fibrillation and tau truncation in human neuroblastoma cells

AUTHOR(S)
Campo, M.; Oliveira, C.; Scheper, W.; Zwart, R.; Korth, C.; Müller-Schiffmann, A.; Kostallas, G.; Biverstal, H.; Presto, J.; Johansson, J.; Hoozemans, J.; Pereira, C.; Teunissen, C.
PUB. DATE
April 2015
SOURCE
Cellular & Molecular Life Sciences;Apr2015, Vol. 72 Issue 8, p1599
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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 (rBRI2) 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 rBRI2 delays Aβ fibril formation, although less efficiently than the BRI2 BRICHOS domain (BRI2 residues 113-231). In human neuroblastoma SH-SY5Y cells, rBRI2 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 upregulated the chaperone BiP but did not modify the mRNA expression of other UPR markers (CHOP and Xbp-1). Strikingly, rBRI2 induced the activation of GSK3β but not the phosphorylation of tau. However, exposure to rBRI2 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.
ACCESSION #
101642186

 

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