Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1–42) Interactions with Calmodulin and Calbindin-D28k
Entity
UAM. Departamento de BioquímicaPublisher
MDPIDate
2022-02-18Citation
10.3390/ijms23042289
International Journal of Molecular Sciences 23.4 (2022): 2289
ISSN
1422-0067 (online); 1661-6596 (print)DOI
10.3390/ijms23042289Funded by
This work has been supported by Grant BFU2017-85723-P of the Spanish Ministerio de Ciencia, Innovación y Universidades (Spanish National R&D program) to Ana M. Mata and Carlos Gutierrez-Merino, and was co-financed by the European Funds for Structural Development (FEDER)Project
Gobierno de España. BFU2017-85723-PEditor's Version
https://doi.org/10.3390/ijms23042289Subjects
Amyloid β; calmodulin; calbindin-D28k; antagonist peptide; Alzheimer’s disease; fluorescence; docking; MedicinaRights
© 2022 by the authorsAbstract
Amyloid β1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ 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) HiLyteTM-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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Google Scholar:Salazar, Jairo
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Poejo, Joana
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Mata, Ana M.
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Samhan Arias, Alejandro Khalil
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Gutierrez-Merino, Carlos
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