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Disrupting Dimeric β-Amyloid by Electric Fields.

ABSTRACT: The early oligomers of the amyloid Aβ peptide are implicated in Alzheimer's disease, but their transient nature complicates the characterization of their structure and toxicity. Here, we investigate the stability of the minimal toxic species, i.e., β-amyloid dimers, in the presence of an oscillating electric field. We first use deep learning (AlphaFold-multimer) for generating initial models of Aβ42 dimers. The flexibility and secondary structure content of the models are then analyzed by multiple runs of molecular dynamics (MD). Structurally stable models are similar to ensemble representatives from microsecond-long MD sampling. Finally, we employ the validated model as the starting structure of MD simulations in the presence of an external oscillating electric field and observe a fast decay of β-sheet content at high field strengths. Control simulations using the helical dimer of the 42-residue leucine zipper peptide show higher structural stability than the Aβ42 dimer. The simulation results provide evidence that an external electric field (oscillating at 1 GHz) can disrupt amyloid oligomers which should be further investigated by experiments with brain organoids in vitro and eventually in vivo.

SUBMITTER: Vargas-Rosales PA

PROVIDER: S-EPMC10540290 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Disrupting Dimeric β-Amyloid by Electric Fields.

Vargas-Rosales Pablo Andrés PA D'Addio Alessio A Zhang Yang Y Caflisch Amedeo A

ACS physical chemistry Au 20230712 5

The early oligomers of the amyloid Aβ peptide are implicated in Alzheimer's disease, but their transient nature complicates the characterization of their structure and toxicity. Here, we investigate the stability of the minimal toxic species, i.e., β-amyloid dimers, in the presence of an oscillating electric field. We first use deep learning (AlphaFold-multimer) for generating initial models of Aβ42 dimers. The flexibility and secondary structure content of the models are then analyzed by multip ...[more]

PMID: 37780539

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Project description:Glioblastoma multiforme (GBM), is the most common form of adult malignant brain tumor, highly heterogeneous and relatively resistant to therapy with a poor prognosis. As other cancers, GBM starts from a relatively small fraction of poorly differentiated and particularly aggressive cancer stem cells (CSCs), responsible for aberrant proliferation and invasion, rapidly spreading the tumor growth in the other parts of the central nervous system. Due to the extreme tumor heterogeneity, standard therapies (i.e., surgery, chemotherapy and radiotherapy) provide poor positive outcomes and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary for searching effective therapeutic strategies against GBM. Among many emerging new therapeutic strategies, ultra-short pulsed electric fields (PEF) are considered extremely promising in cancer therapy and our previous results demonstrated the capability of a specific electric pulse protocol, characterized by a high pulse amplitude and a short duration, to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells, and of U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independently of CSCs content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the clonogenic potential, reducing the ability to form new neurospheres, and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stemness/differentiation genes. Our results, confirm this physical stimulus as a promising treatment to destabilize the extreme intra-tumoral GBM heterogeneity opening up the possibility to develop future therapeutic strategies mediated by PEF exposure.

Dataset Information

Disrupting Dimeric β-Amyloid by Electric Fields.

Publications

Disrupting Dimeric β-Amyloid by Electric Fields.

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