Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1–42) Interactions with Calmodulin and Calbindin-D28k
Amyloid β<sub>1–42</sub> (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca<sup>2+</sup>) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/4/2289 |
| Summary: | Amyloid β<sub>1–42</sub> (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca<sup>2+</sup>) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca<sup>2+</sup> binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1–42) oligomers and extensively binds internalized Aβ(1–42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1–42), using a combined strategy based on the experimental results obtained for Aβ(1–42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1–42) HiLyte<sup>TM</sup>-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1–42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1–42):CaM and of Aβ(1–42):calbindin-D28k complexes. |
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| ISSN: | 1661-6596 1422-0067 |