Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer's ß-Amyloid Fibrillogenesis.
Molecules
; 29(6)2024 Mar 21.
Article
em En
| MEDLINE
| ID: mdl-38543041
ABSTRACT
Design of amyloid ß-protein (Aß) inhibitors is considered an effective strategy for the prevention and treatment of Alzheimer's disease (AD). However, the limited blood-brain barrier (BBB) penetration and poor Aß-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aß-targeting peptide KLVFF and cell-penetrating peptide Penetratin to TTR, and derived a fusion protein, KLVFF-TTR-Penetratin (KTP). Moreover, to introduce the scavenging activity for reactive oxygen species (ROS), a nanocomposite of KTP and manganese dioxide nanoclusters (KTP@MnO2) was fabricated by biomineralization. Results revealed that KTP@MnO2 demonstrated significantly enhanced inhibition on Aß aggregation as compared to TTR. The inhibitory effect was increased from 18%, 33%, and 49% (10, 25, and 50 µg/mL TTR, respectively) to 52%, 81%, and 100% (10, 25, and 50 µg/mL KTP@MnO2). In addition, KTP@MnO2 could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aß-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO2, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO2 at 50 µg/mL increased the viability of Aß-treated cells from 66% to more than 95%, and completely cleared amyloid plaques in AD nematodes and extended their lifespan by 7 d. Overall, despite critical aspects such as the stability, metabolic distribution, long-term biotoxicity, and immunogenicity of the nanocomposites in mammalian models remaining to be investigated, this work has demonstrated the multifunctionality of KTP@MnO2 for targeting Aß in vivo, and provided new insights into the design of multifunctional nanocomposites of protein-metal clusters against AD.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos Penetradores de Células
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Doença de Alzheimer
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article