Membrane-bound tetramer and trimer Aβ oligomeric species correlate with toxicity towards cultured neurons
| Autor: | Chi L.L. Pham, Roberto Cappai, Giuseppe D. Ciccotosto, Metta K. Jana |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Time Factors Amyloid beta Cell Survival Trimer Peptide tau Proteins Plasma protein binding Biochemistry Protein Structure Secondary 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Protein structure Tetramer medicine Animals chemistry.chemical_classification Cerebral Cortex Neurons Amyloid beta-Peptides biology Dose-Response Relationship Drug Chemistry Caspase 3 Neurodegeneration Neurotoxicity medicine.disease Embryo Mammalian Peptide Fragments 030104 developmental biology biology.protein Female Protein Multimerization 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Journal of neurochemistry. 136(3) |
| ISSN: | 1471-4159 |
| Popis: | Amyloid beta (Aβ) peptide is the major constituent of the extracellular amyloid plaques deposited in the brains of Alzheimer's disease patients and is central to the pathogenic pathway causing this disease. The identity of the neurotoxic Aβ species remains elusive. We previously reported that Aβ toxicity correlates strongly with its neuronal cell binding leading us to hypothesize that neuronal cell death is caused by the binding of a specific oligomeric Aβ species. To identify the specific oligomeric Aβ species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic Aβ40 and Aβ42 peptides and identified that the cellular Aβ binding and neurotoxicity were time and concentration dependent. We found a significant correlation between the amount of trimer and tetramer species bound to neurons with increasing neurotoxicity. We prepared Aβ40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Aβ tetramer, followed by the trimer, as the most toxic low-order oligomers Aβ species. Our findings suggested that binding of amyloid-β (Aβ) tetramer and trimer, not monomer or dimer, to neurons is critical to induce neuronal cell death associated with Alzheimer's Disease. We proposed that Aβ trimer and tetramer are the potential neurotoxic Aβ species. This would provide more specific therapeutic target for Alzheimer's Disease. |
| Databáze: | OpenAIRE |
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