Tau Derived Hexapeptide AcPHF6 Promotes Beta-Amyloid (Aβ) Fibrillogenesis
| Autor: | Sarbjeet Singh Gujral, Tarek Mohamed, Praveen P.N. Rao |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Amyloid Physiology Peptidomimetic Cognitive Neuroscience Peptide Protein aggregation Fibril 01 natural sciences Biochemistry Cell Line 03 medical and health sciences chemistry.chemical_compound Alzheimer Disease Humans Neurons chemistry.chemical_classification Amyloid beta-Peptides 010405 organic chemistry Fibrillogenesis Cell Biology General Medicine 0104 chemical sciences 3. Good health 030104 developmental biology Monomer chemistry Cell culture Biophysics Hydrophobic and Hydrophilic Interactions Oligopeptides |
| Zdroj: | ACS Chemical Neuroscience. 9:773-782 |
| ISSN: | 1948-7193 |
| Popis: | We studied the interactions of a tau derived hexapeptide AcPHF6 with β-amyloid peptides Aβ40 and Aβ42 which reveals its unusual ability to promote Aβ fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in Aβ40 and Aβ42 fibril growth. Aggregation kinetic studies at pH 7.4 show that at 25 μM, AcPHF6 hexapeptide was able to cause ∼2.3-fold increase in Aβ40 fibrillogenesis dramatically changing the aggregation kinetics. In addition, AcPHF6 peptide was able to reduce cellular toxicity mediated by Aβ40 and Aβ42 in hippocampal neuronal cell line (HT22). Computational studies suggest that the AcPHF6 peptide can act as an anchor and provides a hydrophobic surface for Aβ monomer to bind and undergo rapid fibrillogenesis to form less toxic fibrils and alter the aggregation kinetics. At the molecular level we propose a "dock-and-pack" mechanism where the AcPHF6 hexapeptide aggregates can stabilize the β-hairpin and promote rapid Aβ self-assembly and growth to form less toxic oligomers or fibrils. Our results have direct implications in designing novel peptide/peptidomimetics as novel pharmacological tools to study protein aggregation and potentially prevent Aβ-mediated toxicity in Alzheimer's disease. |
| Databáze: | OpenAIRE |
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