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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F24%3A00137381" target="_blank" >RIV/00216224:14310/24:00137381 - isvavai.cz</a>

Result on the web

<a href="https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1468602/full" target="_blank" >https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1468602/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fnagi.2024.1468602" target="_blank" >10.3389/fnagi.2024.1468602</a>

Result language

angličtina

Original language name

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

Original language 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 &lt; 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 &lt; 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Frontiers in Aging Neuroscience

ISSN

1663-4365

e-ISSN

1663-4365

Volume of the periodical

16

Issue of the periodical within the volume

October

Country of publishing house

CH - SWITZERLAND

Number of pages

15

Pages from-to

1468602

UT code for WoS article

001348028200001

EID of the result in the Scopus database

2-s2.0-85208649156