TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model

Autores
Basheer, Neha; Muhammadi, Muhammad Khalid; Freites, Carlos Leandro; Avila, Martin; Momand, Miraj Ud Din; Hryntsova, Natalia; Smolek, Tomas; Katina, Stanislav; Zilka, Norbert
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction: Alzheimer’s disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.Results: Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.
Fil: Basheer, Neha. Slovak Academy of Sciences; Eslovaquia
Fil: Muhammadi, Muhammad Khalid. Slovak Academy of Sciences; Eslovaquia
Fil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Momand, Miraj Ud Din. Slovak Academy of Sciences; Eslovaquia
Fil: Hryntsova, Natalia. Slovak Academy of Sciences; Eslovaquia
Fil: Smolek, Tomas. Slovak Academy of Sciences; Eslovaquia
Fil: Katina, Stanislav. Slovak Academy of Sciences; Eslovaquia. Masaryk University; República Checa
Fil: Zilka, Norbert. Slovak Academy of Sciences; Eslovaquia
Materia
ALZHEIMER'S DISEASE
NEUROINFLAMMATION
TAU
LPS
MICROGLIA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/267978

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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse modelBasheer, NehaMuhammadi, Muhammad KhalidFreites, Carlos LeandroAvila, MartinMomand, Miraj Ud DinHryntsova, NataliaSmolek, TomasKatina, StanislavZilka, NorbertALZHEIMER'S DISEASENEUROINFLAMMATIONTAULPSMICROGLIAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Introduction: Alzheimer’s disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.Results: Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.Fil: Basheer, Neha. Slovak Academy of Sciences; EslovaquiaFil: Muhammadi, Muhammad Khalid. Slovak Academy of Sciences; EslovaquiaFil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Momand, Miraj Ud Din. Slovak Academy of Sciences; EslovaquiaFil: Hryntsova, Natalia. Slovak Academy of Sciences; EslovaquiaFil: Smolek, Tomas. Slovak Academy of Sciences; EslovaquiaFil: Katina, Stanislav. Slovak Academy of Sciences; Eslovaquia. Masaryk University; República ChecaFil: Zilka, Norbert. Slovak Academy of Sciences; EslovaquiaFrontiers Media2024-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/267978Basheer, Neha; Muhammadi, Muhammad Khalid; Freites, Carlos Leandro; Avila, Martin; Momand, Miraj Ud Din; et al.; TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model; Frontiers Media; Frontiers in Aging Neuroscience; 16; 10-2024; 1-151663-4365CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fnagi.2024.1468602/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fnagi.2024.1468602info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:18:59Zoai:ri.conicet.gov.ar:11336/267978instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:18:59.713CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
title TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
spellingShingle TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
Basheer, Neha
ALZHEIMER'S DISEASE
NEUROINFLAMMATION
TAU
LPS
MICROGLIA
title_short TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
title_full TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
title_fullStr TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
title_full_unstemmed TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
title_sort TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model
dc.creator.none.fl_str_mv Basheer, Neha
Muhammadi, Muhammad Khalid
Freites, Carlos Leandro
Avila, Martin
Momand, Miraj Ud Din
Hryntsova, Natalia
Smolek, Tomas
Katina, Stanislav
Zilka, Norbert
author Basheer, Neha
author_facet Basheer, Neha
Muhammadi, Muhammad Khalid
Freites, Carlos Leandro
Avila, Martin
Momand, Miraj Ud Din
Hryntsova, Natalia
Smolek, Tomas
Katina, Stanislav
Zilka, Norbert
author_role author
author2 Muhammadi, Muhammad Khalid
Freites, Carlos Leandro
Avila, Martin
Momand, Miraj Ud Din
Hryntsova, Natalia
Smolek, Tomas
Katina, Stanislav
Zilka, Norbert
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALZHEIMER'S DISEASE
NEUROINFLAMMATION
TAU
LPS
MICROGLIA
topic ALZHEIMER'S DISEASE
NEUROINFLAMMATION
TAU
LPS
MICROGLIA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Introduction: Alzheimer’s disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.Results: Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.
Fil: Basheer, Neha. Slovak Academy of Sciences; Eslovaquia
Fil: Muhammadi, Muhammad Khalid. Slovak Academy of Sciences; Eslovaquia
Fil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Momand, Miraj Ud Din. Slovak Academy of Sciences; Eslovaquia
Fil: Hryntsova, Natalia. Slovak Academy of Sciences; Eslovaquia
Fil: Smolek, Tomas. Slovak Academy of Sciences; Eslovaquia
Fil: Katina, Stanislav. Slovak Academy of Sciences; Eslovaquia. Masaryk University; República Checa
Fil: Zilka, Norbert. Slovak Academy of Sciences; Eslovaquia
description Introduction: Alzheimer’s disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.Results: Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.
publishDate 2024
dc.date.none.fl_str_mv 2024-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/267978
Basheer, Neha; Muhammadi, Muhammad Khalid; Freites, Carlos Leandro; Avila, Martin; Momand, Miraj Ud Din; et al.; TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model; Frontiers Media; Frontiers in Aging Neuroscience; 16; 10-2024; 1-15
1663-4365
CONICET Digital
CONICET
url http://hdl.handle.net/11336/267978
identifier_str_mv Basheer, Neha; Muhammadi, Muhammad Khalid; Freites, Carlos Leandro; Avila, Martin; Momand, Miraj Ud Din; et al.; TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model; Frontiers Media; Frontiers in Aging Neuroscience; 16; 10-2024; 1-15
1663-4365
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fnagi.2024.1468602/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fnagi.2024.1468602
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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