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Publication Detail
Exploring the role of BIN1 in Alzheimer’s disease
  • Publication Type:
  • Authors:
    Gabriele R, Glennon E, Wray S, Lines G
  • Presented date:
  • Presented at:
    AAIC 2020
  • Keywords:
    AD, UPR, Bridging Integrator 1
  • Addresses:
    Cruciform Building
    University College London
    Institute of Neurology
    Gower Street
    WC1E 6AE
    United Kingdom
Background: Bridging integrator 1 (BIN1) is a major risk factor for Alzheimer’s dis ease (AD). In the brain BIN1 is expressed by neurons and glial cells with each cell type expressing specific isoforms. Interestingly, previous studies have shown that BIN1 expression is altered in AD brains. However, little is known on how each individual iso form is affected and how BIN1 contributes to AD pathogenesis. Our preliminary data suggests that the neuronal isoforms of BIN1 (nBIN1) may modulate the unfolded pro tein response (UPR), an endoplasmic reticulum stress triggered mechanism. The UPR consists of three different signalling pathways regulated by: PERK, IRE1 and the tran scription factor ATF6, which is cleaved into an active form which translocates to the nucleus. Interestingly, the UPR is thought to play a role in AD pathogenesis. This study examines the role of BIN1 in AD as UPR modulator. Method: Effects of BIN1 expression on UPR activation was investigated by means of western blot and immunocytochemistry in SH-SY5Y cells expressing nBIN1 or an empty vector. To detect the ATF6 fragment, western blot was carried out on HEK cells expressing BIN1 or an empty vector co-transfected with an ATF6-GFP construct. Effects of BIN1 downregulation was explored by luciferase assay and immunocyto chemistry in N2a cells transfected with BIN1 or control siRNA Result:Increased expression of BIN1 showed a significant decrease in full-length ATF6, an increase in the cleaved fragment of ATF6, an increase in the ATF6 target gene Bip and a significant increase in ATF6 nuclear translocation compared to control, suggest ing a selective activation of the ATF6 arm of the UPR. Interestingly, downregulation of BIN1 in N2a shows a selective inhibition of the ATF6 pathway. Conclusion: UPR dysregulation is a salient feature in AD; we explored the involvement of BIN1 in the regulation of the UPR and found that altered levels of BIN1 can selectively modulate the ATF6 pathway. Future studies to dissect the relationship between BIN1 and ATF6 and better understand the underlying mechanisms might offer an insight into future therapeutic targets.
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