Interactions between BIM Protein and Beta-Amyloid May Reveal a Crucial Missing Link between Alzheimer's Disease and Neuronal Cell Death

Ravit Malishev, Sukhendu Nandi, Dariusz Śmiłowicz, Shamchal Bakavayev, Stanislav Engel, Nir Bujanover, Roi Gazit, Nils Metzler-Nolte, Raz Jelinek

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Extensive neuronal cell death is among the pathological hallmarks of Alzheimer's disease. While neuron death is coincident with formation of plaques comprising the beta-amyloid (Aβ) peptide, a direct causative link between Aβ (or other Alzheimer's-associated proteins) and cell toxicity is yet to be found. Here we show that BIM-BH3, the primary proapoptotic domain of BIM, a key protein in varied apoptotic cascades of which elevated levels have been found in brain cells of patients afflicted with Alzheimer's disease, interacts with the 42-residue amyloid isoform Aβ42. Remarkably, BIM-BH3 modulated the structure, fibrillation pathway, aggregate morphology, and membrane interactions of Aβ42. In particular, BIM-BH3 inhibited Aβ42 fibril-formation, while it simultaneously enhanced protofibril assembly. Furthermore, we discovered that BIM-BH3/Aβ42 interactions induced cell death in a human neuroblastoma cell model. Overall, our data provide a crucial mechanistic link accounting for neuronal cell death in Alzheimer's disease patients and the participation of both BIM and Aβ42 in the neurotoxicity process.

Original languageEnglish
Pages (from-to)3555-3564
Number of pages10
JournalACS Chemical Neuroscience
Volume10
Issue number8
DOIs
StatePublished - 21 Aug 2019

Keywords

  • BIM
  • Bcl-3 homology 3
  • Beta-amyloid
  • amyloid/membrane interaction
  • apoptosis
  • mitochondria

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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