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Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we perfo...

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Autores principales: Bai, Ping, Mondal, Prasenjit, Bagdasarian, Frederick A., Rani, Nisha, Liu, Yan, Gomm, Ashley, Tocci, Darcy R., Choi, Se Hoon, Wey, Hsiao-Ying, Tanzi, Rudolph E., Zhang, Can, Wang, Changning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532562/
https://www.ncbi.nlm.nih.gov/pubmed/36213537
http://dx.doi.org/10.1016/j.apsb.2022.05.017
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author Bai, Ping
Mondal, Prasenjit
Bagdasarian, Frederick A.
Rani, Nisha
Liu, Yan
Gomm, Ashley
Tocci, Darcy R.
Choi, Se Hoon
Wey, Hsiao-Ying
Tanzi, Rudolph E.
Zhang, Can
Wang, Changning
author_facet Bai, Ping
Mondal, Prasenjit
Bagdasarian, Frederick A.
Rani, Nisha
Liu, Yan
Gomm, Ashley
Tocci, Darcy R.
Choi, Se Hoon
Wey, Hsiao-Ying
Tanzi, Rudolph E.
Zhang, Can
Wang, Changning
author_sort Bai, Ping
collection PubMed
description Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.
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spelling pubmed-95325622022-10-06 Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease Bai, Ping Mondal, Prasenjit Bagdasarian, Frederick A. Rani, Nisha Liu, Yan Gomm, Ashley Tocci, Darcy R. Choi, Se Hoon Wey, Hsiao-Ying Tanzi, Rudolph E. Zhang, Can Wang, Changning Acta Pharm Sin B Original Article Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology. Elsevier 2022-10 2022-05-20 /pmc/articles/PMC9532562/ /pubmed/36213537 http://dx.doi.org/10.1016/j.apsb.2022.05.017 Text en © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Bai, Ping
Mondal, Prasenjit
Bagdasarian, Frederick A.
Rani, Nisha
Liu, Yan
Gomm, Ashley
Tocci, Darcy R.
Choi, Se Hoon
Wey, Hsiao-Ying
Tanzi, Rudolph E.
Zhang, Can
Wang, Changning
Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title_full Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title_fullStr Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title_full_unstemmed Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title_short Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
title_sort development of a potential pet probe for hdac6 imaging in alzheimer's disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532562/
https://www.ncbi.nlm.nih.gov/pubmed/36213537
http://dx.doi.org/10.1016/j.apsb.2022.05.017
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