Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
Department of Medical Neurobiology (Physiology), The Hebrew University of Jerusalem, Hadassah Medical Faculty, Jerusalem, Israel 91120.
J Am Chem Soc. 2023 Feb 15;145(6):3543-3553. doi: 10.1021/jacs.2c12305. Epub 2023 Feb 3.
Alzheimer's disease is one of the most common neurodegenerative conditions, which are ascribed to extracellular accumulation of β-amyloid peptides into plaques. This phenomenon seems to typify other related neurodegenerative diseases. The present study uses classical molecular-dynamics simulations to decipher the aggregation-disintegration behavior of β-amyloid peptide plaques in the presence of static and oscillating oriented external electric fields (OEEFs). A long-term disintegration of such plaques is highly desirable since this may improve the prospects of therapeutic treatments of Alzheimer's disease and of other neurodegenerative diseases typified by senile plaques. Our study illustrates the spontaneous aggregation of the β-amyloid, its prevention and breakdown when OEEF is applied, and the fate of the broken aggregate when the OEEF is removed. Notably, we demonstrate that the usage of an oscillating OEEF on β-amyloid aggregates appears to lead to an irreversible disintegration. Insight is provided into the root causes of the various modes of aggregation, as well as into the different fates of OEEF-induced disintegration in oscillating vs static fields. Finally, our simulation results are compared to the well-established TTFields and the Deep Brain Stimulation (DBS) therapies, which are currently used options for treatments of Alzheimer's disease and other related neurodegenerative diseases.
阿尔茨海默病是最常见的神经退行性疾病之一,其特征是β-淀粉样肽在斑块中外泌体积累。这种现象似乎是其他相关神经退行性疾病的典型特征。本研究使用经典分子动力学模拟来破译β-淀粉样肽斑块在静态和振荡定向外电场(OEEF)存在下的聚集-解体行为。这种斑块的长期解体是非常可取的,因为这可能改善阿尔茨海默病和以老年斑为特征的其他神经退行性疾病的治疗前景。我们的研究说明了β-淀粉样蛋白的自发聚集,以及当施加 OEEF 时的预防和分解,以及当去除 OEEF 时破碎聚集体的命运。值得注意的是,我们证明了在β-淀粉样蛋白聚集体上使用振荡 OEEF 似乎会导致不可逆转的解体。深入了解了各种聚集模式的根本原因,以及振荡和静态场中 OEEF 诱导的解体的不同命运。最后,我们的模拟结果与现有的 TTFields 和深部脑刺激(DBS)疗法进行了比较,这些疗法是目前用于治疗阿尔茨海默病和其他相关神经退行性疾病的选择。