Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease
Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Recursos: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/51929 |
| Acesso em linha: | http://hdl.handle.net/10810/51929 |
| Access Level: | acceso abierto |
| Palavra-chave: | butyrylcholinesterase PET positron emission tomography alzheimer disease amyloid beta |
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Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| title |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| spellingShingle |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease Rejc, Luka butyrylcholinesterase PET positron emission tomography alzheimer disease amyloid beta |
| title_short |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| title_full |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| title_fullStr |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| title_full_unstemmed |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| title_sort |
Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer Disease |
| dc.creator.none.fl_str_mv |
Rejc, Luka Gómez Vallejo, Vanessa Joya, Ana Moreno, Oscar Egimendia Tolaretxipi, Ander Castellnou Arenas, Pilar Ríos Anglada, Xabier Cossío Arrieta, Unai Baz Maldonado, Zuriñe Passannante, Rossana Tobalina Larrea, Ignacio Ramos Cabrer, Pedro Giralt, Albert Sastre, Magdalena Capetillo González de Zárate, Estíbaliz Košak, Urban Knez, Damijan Gobec, Stanislav Marder, Mariel Martín Muñoz, Abraham Llop Roig, Jordi |
| author |
Rejc, Luka |
| author_facet |
Rejc, Luka Gómez Vallejo, Vanessa Joya, Ana Moreno, Oscar Egimendia Tolaretxipi, Ander Castellnou Arenas, Pilar Ríos Anglada, Xabier Cossío Arrieta, Unai Baz Maldonado, Zuriñe Passannante, Rossana Tobalina Larrea, Ignacio Ramos Cabrer, Pedro Giralt, Albert Sastre, Magdalena Capetillo González de Zárate, Estíbaliz Košak, Urban Knez, Damijan Gobec, Stanislav Marder, Mariel Martín Muñoz, Abraham Llop Roig, Jordi |
| author_role |
author |
| author2 |
Gómez Vallejo, Vanessa Joya, Ana Moreno, Oscar Egimendia Tolaretxipi, Ander Castellnou Arenas, Pilar Ríos Anglada, Xabier Cossío Arrieta, Unai Baz Maldonado, Zuriñe Passannante, Rossana Tobalina Larrea, Ignacio Ramos Cabrer, Pedro Giralt, Albert Sastre, Magdalena Capetillo González de Zárate, Estíbaliz Košak, Urban Knez, Damijan Gobec, Stanislav Marder, Mariel Martín Muñoz, Abraham Llop Roig, Jordi |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
butyrylcholinesterase PET positron emission tomography alzheimer disease amyloid beta |
| topic |
butyrylcholinesterase PET positron emission tomography alzheimer disease amyloid beta |
| description |
Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10810/51929 |
| url |
http://hdl.handle.net/10810/51929 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
info:eu-repo/grantAgreement/MICINN/CTQ2017-87637-R/ info:eu-repo/grantAgreement/MICINN/SAF2017-87670-R/ info:eu-repo/grantAgreement/MICINN/PID2019-107989RB-I00/ info:eu-repo/grantAgreement/MICINN/RYC-2017-22412/ info:eu-repo/grantAgreement/MICINN/MDM-2017-0720/ info:eu-repo/grantAgreement/MICINN/RTI2018-094678-A-I00/ info:eu-repo/grantAgreement/MICINN/RYC-2016-19466/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120209/ |
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info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/3.0/es/ Atribución 3.0 España |
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openAccess |
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http://creativecommons.org/licenses/by/3.0/es/ Atribución 3.0 España |
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application/pdf |
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Ivyspring International Publisher |
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Ivyspring International Publisher |
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reponame:Addi. Archivo Digital para la Docencia y la Investigación instname:Universidad del País Vasco |
| instname_str |
Universidad del País Vasco |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Longitudinal Evaluation of a Novel BChE PET Tracer as An Early In Vivo Biomarker in the Brain of a Mouse Model for Alzheimer DiseaseRejc, LukaGómez Vallejo, VanessaJoya, AnaMoreno, OscarEgimendia Tolaretxipi, AnderCastellnou Arenas, PilarRíos Anglada, XabierCossío Arrieta, UnaiBaz Maldonado, ZuriñePassannante, RossanaTobalina Larrea, IgnacioRamos Cabrer, PedroGiralt, AlbertSastre, MagdalenaCapetillo González de Zárate, EstíbalizKošak, UrbanKnez, DamijanGobec, StanislavMarder, MarielMartín Muñoz, AbrahamLlop Roig, JordibutyrylcholinesterasePETpositron emission tomographyalzheimer diseaseamyloid betaPurpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD.J.L., P. R. and A.M thank the Spanish Ministry of Economy and Competitiveness (Project numbers: CTQ2017-87637-R, SAF2017-87670-R, PID2019-107989RB-I00 and RYC-2017-22412, respectively) and the Basque Government (project number: 2019RTE00214647-2019222012) for financial support. L.R., U.K. and S.G. thank the Slovenian Research Agency (projects J1-9166, Z1-9195, L1-8157 and NC-0009; research programs P1-0230 and P1-0208 for core financing). M.M. thanks Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP Number 112 201501 00410, P-UE Number 22920160100046CO) and Universidad de Buenos Aires (UBA, UBACyT Number 20020150100012BA) for financial support. Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720), and co-financed by the Interreg Atlantic Area Programme through the European Regional Development Fund. A. G. was supported by a grant from Ministerio de Ciencia, Innovación y Universidades (RTI2018-094678-A-I00) and he is a Ramón y Cajal fellow (RYC-2016-19466). E.C-Z. thanks the Basque Government (KK-2020/00034) for financial support.Ivyspring International Publisher202120212021info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/51929reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN/CTQ2017-87637-R/info:eu-repo/grantAgreement/MICINN/SAF2017-87670-R/info:eu-repo/grantAgreement/MICINN/PID2019-107989RB-I00/info:eu-repo/grantAgreement/MICINN/RYC-2017-22412/info:eu-repo/grantAgreement/MICINN/MDM-2017-0720/info:eu-repo/grantAgreement/MICINN/RTI2018-094678-A-I00/info:eu-repo/grantAgreement/MICINN/RYC-2016-19466/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120209/info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0)Atribución 3.0 Españaoai:addi.ehu.eus:10810/519292026-06-18T09:23:17Z |
| score |
15.301603 |