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An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Porphyromonas gingivalis outer membrane vesicles alter cortical neurons and Tau phosphorylation in the embryonic
Adrienne J Bradley1, Lauren Mashburn-Warren1, Lexie C Blalock1
1Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
Insights
Exposure to Porphyromonas gingivalis outer membrane vesicles (Pg-OMV) during pregnancy reduced fetal brain weight and altered neuron density. This study highlights potential risks of oral bacteria to offspring brain development.
Area of Science:
- Neuroscience
- Microbiology
- Developmental Biology
Background:
- Porphyromonas gingivalis (Pg) is an oral pathogen linked to systemic inflammation and adverse pregnancy outcomes.
- Pg virulence factors are found on outer membrane vesicles (OMV) that may spread systemically.
- The impact of Pg-OMV on fetal brain development during pregnancy is not well understood.
Purpose of the Study:
- To investigate the effects of Pg-OMV exposure on the developing fetal brain in a mouse model.
- To assess changes in brain weight, inflammation, neuronal density, and Tau phosphorylation.
Main Methods:
- Pregnant C57/Bl6 mice were treated with Pg-OMV or PBS via tail vein injection from gestational age 3 to 17.
- Pup brains were collected at gestational age 18.5 for analysis.
- Measurements included brain weight, microglia activation (Iba-1), cytokine mRNA and protein levels, cortical neuron markers (Cux1, SatB2), and phosphorylated Tau (p-Tau Thr231).
Main Results:
- Pg-OMV exposure significantly decreased pup brain weight.
- Microglia activation (Iba-1) increased, but overall pro-inflammatory cytokine mRNA levels remained unchanged; IL-6 protein was lower.
- Cortical neuron density (Cux1, SatB2) decreased, and p-Tau Thr231 levels were elevated in Pg-OMV exposed offspring brains.
Conclusions:
- Pg-OMV exposure during gestation can significantly alter embryonic brain development.
- These findings suggest Porphyromonas gingivalis may impact offspring neurodevelopment through mechanisms involving its outer membrane vesicles.
- Further research is warranted to elucidate the specific pathways and long-term consequences.
Abstract:
Porphyromonas gingivalis (Pg) is an oral bacterial pathogen that has been associated with systemic inflammation and adverse pregnancy outcomes such as low birth weight and pre-term birth. Pg drives these sequelae through virulence factors decorating the outer membrane that are present on non-replicative outer membrane vesicles (OMV) that are suspected to be transmitted systemically. Given that Pg abundance can increase during pregnancy, it is not well known whether Pg-OMV can have deleterious effects on the brain of the developing fetus. We tested this possibility by treating pregnant C57/Bl6 mice with PBS (control) and OMV from ATCC 33277 by tail vein injection every other day from gestational age 3 to 17. At gestational age 18.5, we measured dam and pup weights and collected pup brains to quantify changes in inflammation, cortical neuron density, and Tau phosphorylated at Thr231. Dam and pup weights were not altered by Pg-OMV exposure, but pup brain weight was significantly decreased in the Pg-OMV treatment group. We found a significant increase of Iba-1, indicative of microglia activation, although the overall levels of IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ mRNA transcripts were not different between the treatment groups. Differences in IL-1β, IL-6, and TNFα concentrations by ELISA showed IL-6 was significantly lower in Pg-OMV brains. Cortical neuron density was modified by treatment with Pg-OMV as immunofluorescence showed significant decreases in Cux1 and SatB2. Overall p-Tau Thr231 was increased in the brains of pups whose mothers were exposed to Pg-OMV. Together these results demonstrate that Pg-OMV can significantly modify the embryonic brain and suggests that Pg may impact offspring development via multiple mechanisms.
