Interactions between BIM Protein and Beta-Amyloid May Reveal a Crucial Missing Link between Alzheimer's Disease and Neuronal Cell Death.
Ravit MalishevSukhendu NandiDariusz ŚmiłowiczShamchal BakavayevStanislav EngelNir BujanoverRoi GazitNils Metzler NolteRaz JelinekPublished in: ACS chemical neuroscience (2019)
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.
Keyphrases
- cell death
- cell cycle arrest
- end stage renal disease
- cognitive decline
- newly diagnosed
- chronic kidney disease
- prognostic factors
- peritoneal dialysis
- gene expression
- oxidative stress
- binding protein
- patient reported outcomes
- cell therapy
- protein protein
- induced apoptosis
- machine learning
- mesenchymal stem cells
- artificial intelligence
- mild cognitive impairment
- big data
- signaling pathway
- deep learning
- pi k akt
- drug induced
- endoplasmic reticulum stress