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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/267978
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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/ |
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openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
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application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Frontiers Media |
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Frontiers Media |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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13.070432 |