Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis

Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Haitao Lan [verfasserIn] Ying Wang [verfasserIn] Wei Liu [verfasserIn] Xiaoyan Dong [verfasserIn] Yan Sun [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 29(2024), 6, p 1405
Übergeordnetes Werk:	volume:29 ; year:2024 ; number:6, p 1405

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules29061405

Katalog-ID:	DOAJ100456073

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allfields	10.3390/molecules29061405 doi (DE-627)DOAJ100456073 (DE-599)DOAJfc26827210a84940bb8d7bd5b21caa1a DE-627 ger DE-627 rakwb eng QD241-441 Haitao Lan verfasserin aut Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry Ying Wang verfasserin aut Wei Liu verfasserin aut Xiaoyan Dong verfasserin aut Yan Sun verfasserin aut In Molecules MDPI AG, 2003 29(2024), 6, p 1405 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:29 year:2024 number:6, p 1405 https://doi.org/10.3390/molecules29061405 kostenfrei https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a kostenfrei https://www.mdpi.com/1420-3049/29/6/1405 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 29 2024 6, p 1405
spelling	10.3390/molecules29061405 doi (DE-627)DOAJ100456073 (DE-599)DOAJfc26827210a84940bb8d7bd5b21caa1a DE-627 ger DE-627 rakwb eng QD241-441 Haitao Lan verfasserin aut Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry Ying Wang verfasserin aut Wei Liu verfasserin aut Xiaoyan Dong verfasserin aut Yan Sun verfasserin aut In Molecules MDPI AG, 2003 29(2024), 6, p 1405 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:29 year:2024 number:6, p 1405 https://doi.org/10.3390/molecules29061405 kostenfrei https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a kostenfrei https://www.mdpi.com/1420-3049/29/6/1405 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 29 2024 6, p 1405
allfields_unstemmed	10.3390/molecules29061405 doi (DE-627)DOAJ100456073 (DE-599)DOAJfc26827210a84940bb8d7bd5b21caa1a DE-627 ger DE-627 rakwb eng QD241-441 Haitao Lan verfasserin aut Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry Ying Wang verfasserin aut Wei Liu verfasserin aut Xiaoyan Dong verfasserin aut Yan Sun verfasserin aut In Molecules MDPI AG, 2003 29(2024), 6, p 1405 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:29 year:2024 number:6, p 1405 https://doi.org/10.3390/molecules29061405 kostenfrei https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a kostenfrei https://www.mdpi.com/1420-3049/29/6/1405 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 29 2024 6, p 1405
allfieldsGer	10.3390/molecules29061405 doi (DE-627)DOAJ100456073 (DE-599)DOAJfc26827210a84940bb8d7bd5b21caa1a DE-627 ger DE-627 rakwb eng QD241-441 Haitao Lan verfasserin aut Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry Ying Wang verfasserin aut Wei Liu verfasserin aut Xiaoyan Dong verfasserin aut Yan Sun verfasserin aut In Molecules MDPI AG, 2003 29(2024), 6, p 1405 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:29 year:2024 number:6, p 1405 https://doi.org/10.3390/molecules29061405 kostenfrei https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a kostenfrei https://www.mdpi.com/1420-3049/29/6/1405 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 29 2024 6, p 1405
allfieldsSound	10.3390/molecules29061405 doi (DE-627)DOAJ100456073 (DE-599)DOAJfc26827210a84940bb8d7bd5b21caa1a DE-627 ger DE-627 rakwb eng QD241-441 Haitao Lan verfasserin aut Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry Ying Wang verfasserin aut Wei Liu verfasserin aut Xiaoyan Dong verfasserin aut Yan Sun verfasserin aut In Molecules MDPI AG, 2003 29(2024), 6, p 1405 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:29 year:2024 number:6, p 1405 https://doi.org/10.3390/molecules29061405 kostenfrei https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a kostenfrei https://www.mdpi.com/1420-3049/29/6/1405 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 29 2024 6, p 1405
language	English
source	In Molecules 29(2024), 6, p 1405 volume:29 year:2024 number:6, p 1405
sourceStr	In Molecules 29(2024), 6, p 1405 volume:29 year:2024 number:6, p 1405
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration Organic chemistry
isfreeaccess_bool	true
container_title	Molecules
authorswithroles_txt_mv	Haitao Lan @@aut@@ Ying Wang @@aut@@ Wei Liu @@aut@@ Xiaoyan Dong @@aut@@ Yan Sun @@aut@@
publishDateDaySort_date	2024-01-01T00:00:00Z
hierarchy_top_id	311313132
id	DOAJ100456073
language_de	englisch
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callnumber-first	Q - Science
author	Haitao Lan
spellingShingle	Haitao Lan misc QD241-441 misc Alzheimer’s disease misc amyloid β-protein misc transthyretin misc manganese dioxide nanoclusters misc BBB penetration misc Organic chemistry Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis
authorStr	Haitao Lan
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topic_title	QD241-441 Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis Alzheimer’s disease amyloid β-protein transthyretin manganese dioxide nanoclusters BBB penetration
topic	misc QD241-441 misc Alzheimer’s disease misc amyloid β-protein misc transthyretin misc manganese dioxide nanoclusters misc BBB penetration misc Organic chemistry
topic_unstemmed	misc QD241-441 misc Alzheimer’s disease misc amyloid β-protein misc transthyretin misc manganese dioxide nanoclusters misc BBB penetration misc Organic chemistry
topic_browse	misc QD241-441 misc Alzheimer’s disease misc amyloid β-protein misc transthyretin misc manganese dioxide nanoclusters misc BBB penetration misc Organic chemistry
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title	Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis
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title_full	Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis
author_sort	Haitao Lan
journal	Molecules
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author_browse	Haitao Lan Ying Wang Wei Liu Xiaoyan Dong Yan Sun
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author-letter	Haitao Lan
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title_sort	composite of klvff-transthyretin-penetratin and manganese dioxide nanoclusters: a multifunctional agent against alzheimer’s β-amyloid fibrillogenesis
callnumber	QD241-441
title_auth	Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis
abstract	Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD.
abstractGer	Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD.
abstract_unstemmed	Design of amyloid β-protein (Aβ) 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 Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-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 (KTPMnO<sub<2</sub<) was fabricated by biomineralization. Results revealed that KTP@MnO<sub<2</sub< demonstrated significantly enhanced inhibition on Aβ 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@MnO<sub<2</sub<). In addition, KTP@MnO<sub<2</sub< could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO<sub<2</sub<, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO<sub<2</sub< at 50 μg/mL increased the viability of Aβ-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@MnO<sub<2</sub< for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
container_issue	6, p 1405
title_short	Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis
url	https://doi.org/10.3390/molecules29061405 https://doaj.org/article/fc26827210a84940bb8d7bd5b21caa1a https://www.mdpi.com/1420-3049/29/6/1405 https://doaj.org/toc/1420-3049
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up_date	2024-07-03T14:46:10.169Z
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