Multiple Function Fluorescein Probe Performs Metal Chelation, Disaggregation, and Modulation of Aggregated A尾 and A尾-Cu Complex

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• 作者：B. Muthuraj ; Sourav Layek ; S. N. Balaji ; Vishal Trivedi ; Parameswar Krishnan Iyer
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：November 18, 2015
• 年：2015
• 卷：6
• 期：11
• 页码：1880-1891
• 全文大小：660K
• ISSN：1948-7193

文摘

An exceptional probe comprising indole-3-carboxaldehyde fluorescein hydrazone (FI) performs multiple tasks, namely, disaggregating amyloid 尾 (A尾) aggregates in different biomarker environments such as cerebrospinal fluid (CSF), A尾1鈥?0 fibrils, 尾-amyloid lysozyme aggregates (LA), and U87 MG human astrocyte cells. Additionally, the probe FI binds with Cu²⁺ ions selectively, disrupts the A尾 aggregates that vary from few nanometers to micrometers, and prevents their reaggregation, thereby performing disaggregation and modulation of amyloid-尾 in the presence as well as absence of Cu²⁺ ion. The excellent selectivity of probe FI for Cu²⁺ was effectively utilized to modulate the assembly of metal-induced A尾 aggregates by metal chelation with the 鈥渢urn-on鈥?fluorescence via spirolactam ring opening of FI as well as the metal-free A尾 fibrils by noncovalent interactions. These results confirm that FI has exceptional ability to perform multifaceted tasks such as metal chelation in intracellular conditions using A尾 lysozyme aggregates in cellular environments by the disruption of 尾-sheet rich A尾 fibrils into disaggregated forms. Subsequently, it was confirmed that FI had the ability to cross the blood-brain barrier and it also modulated the metal induced A尾 fibrils in cellular environments by 鈥渢urn-on鈥?fluorescence, which are the most vital properties of a probe or a therapeutic agent. Furthermore, the morphology changes were examined by atomic force microscopy (AFM), polarizable optical microscopy (POM), fluorescence microscopy, and dynamic light scattering (DLS) studies. These results provide very valuable clues on the A尾 (CSF A尾 fibrils, A尾1鈥?0 fibrils, 尾-amyloid lysozyme aggregates) disaggregation behavior via in vitro studies, which constitute the first insights into intracellular disaggregation of A尾 by 鈥渢urn-on鈥?method thereby influencing amyloidogenesis.