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Research article
Ivana Grković
University of Belgrade Vinca Institute of Nuclear Science
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4476-7871
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
The present study aims to explore the involvement of purinergic signaling in the rodent model of hippocampal degeneration induced by trimethyltin (TMT), which results in behavioral and neurological dysfunction similar to Alzheimer’s disease. Our study has provided novel evidence that TMT induced extracellular depositions of amyloid β, which might be the cause of the well-defined progressive hippocampal neurodegeneration and gliosis.
Methods
We have applied enzyme histochemistry and immunohistochemistry to study spatial and temporal patterns of ectonucleotidase NTPDase1/CD39 and eN/CD73 expression, gene expression analysis and immunochemistry to analyze cellular localization of select purinoreceptors and pro-inflammatory cytokines previously associated with microglia and astrocytes activation.
Results
Our study demonstrated that all Iba1-ir microglial cells, irrespective of the cell shape and localization, upregulated NTPDase1/CD39, while the induction of eN/CD73 has been observed only at amoeboid microglia, localized within the hippocampal layers with pronounced cell death. Marked induction of P2Y12R and P2Y6R at amoeboid microglia might reflect the transition from rod to amoeboid microglia and the adaptation to the migratory and phagocytic properties of the latter. Based on the expression of the microglial polarization markers, the majority of microglia belonged to the M2-like functional state. A significant change in purinergic signaling components accompanied the response of reactive astrocytes, which occupied the areas with pronounced cell death. Reactive astrocytes, which markedly expressed adenosine A2A and P2Y1 receptors, showed massive induction of complement component C3, NF-kB and IL-1β, suggesting that astrocyte-derived inflammation might be responsible for prolonged and spreading neurodegeneration in TMT model.
Conclusion
This study put glia-associated purinergic signaling in the center of molecular pathogenesis of AD-like disease. Our findings suggest that the ectonucleotidases and purinergic signaling play significant role in microgliosis, astrocyte-driven neuroinflammation and prolonged neurodegeneration in the TMT model.
Keywords
hippocampus, neurodegeneration, purinergic receptors, microglial polarization, NTPDase1/CD39, eN/CD73, astrocyte-derived inflammation
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This is a preprint. It has not completed peer review.
Research article
Ivana Grković
University of Belgrade Vinca Institute of Nuclear Science
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4476-7871
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 29 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Molecular Genetics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
The present study aims to explore the involvement of purinergic signaling in the rodent model of hippocampal degeneration induced by trimethyltin (TMT), which results in behavioral and neurological dysfunction similar to Alzheimer’s disease. Our study has provided novel evidence that TMT induced extracellular depositions of amyloid β, which might be the cause of the well-defined progressive hippocampal neurodegeneration and gliosis.
Methods
We have applied enzyme histochemistry and immunohistochemistry to study spatial and temporal patterns of ectonucleotidase NTPDase1/CD39 and eN/CD73 expression, gene expression analysis and immunochemistry to analyze cellular localization of select purinoreceptors and pro-inflammatory cytokines previously associated with microglia and astrocytes activation.
Results
Our study demonstrated that all Iba1-ir microglial cells, irrespective of the cell shape and localization, upregulated NTPDase1/CD39, while the induction of eN/CD73 has been observed only at amoeboid microglia, localized within the hippocampal layers with pronounced cell death. Marked induction of P2Y12R and P2Y6R at amoeboid microglia might reflect the transition from rod to amoeboid microglia and the adaptation to the migratory and phagocytic properties of the latter. Based on the expression of the microglial polarization markers, the majority of microglia belonged to the M2-like functional state. A significant change in purinergic signaling components accompanied the response of reactive astrocytes, which occupied the areas with pronounced cell death. Reactive astrocytes, which markedly expressed adenosine A2A and P2Y1 receptors, showed massive induction of complement component C3, NF-kB and IL-1β, suggesting that astrocyte-derived inflammation might be responsible for prolonged and spreading neurodegeneration in TMT model.
Conclusion
This study put glia-associated purinergic signaling in the center of molecular pathogenesis of AD-like disease. Our findings suggest that the ectonucleotidases and purinergic signaling play significant role in microgliosis, astrocyte-driven neuroinflammation and prolonged neurodegeneration in the TMT model.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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