Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease
<p>Abstract</p> <p>Background</p> <p>Numerous epidemiological studies demonstrate that genetic background modifies the onset and the progression of Alzheimer's disease and related neurodegenerative disorders. The efficacious influence of genetic background on the d...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-10-01
|
| Series: | Journal of Neuroinflammation |
| Online Access: | http://www.jneuroinflammation.com/content/7/1/64 |
| _version_ | 1818447170807791616 |
|---|---|
| author | Kovacech Branislav Novak Petr Zilka Norbert Stozicka Zuzana Bugos Ondrej Novak Michal |
| author_facet | Kovacech Branislav Novak Petr Zilka Norbert Stozicka Zuzana Bugos Ondrej Novak Michal |
| author_sort | Kovacech Branislav |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Numerous epidemiological studies demonstrate that genetic background modifies the onset and the progression of Alzheimer's disease and related neurodegenerative disorders. The efficacious influence of genetic background on the disease pathway of amyloid beta has been meticulously described in rodent models. Since the impact of genetic modifiers on the neurodegenerative and neuroinflammatory cascade induced by misfolded tau protein is yet to be elucidated, we have addressed the issue by using transgenic lines expressing the same human truncated tau protein in either spontaneously hypertensive rat (SHR) or Wistar-Kyoto (WKY) genetic background.</p> <p>Methods</p> <p>Brains of WKY and SHR transgenic rats in the terminal stage of phenotype and their age-matched non-transgenic littermates were examined by means of immunohistochemistry and unbiased stereology. Basic measures of tau-induced neurodegeneration (load of neurofibrillary tangles) and neuroinflammation (number of Iba1-positive microglia, their activated morphology, and numbers of microglia immunoreactive for MHCII and astrocytes immunoreactive for GFAP) were quantified with an optical fractionator in brain areas affected by neurofibrillary pathology (pons, medulla oblongata). The stereological data were evaluated using two-way ANOVA and Student's t-test.</p> <p>Results</p> <p>Tau neurodegeneration (neurofibrillary tangles (NFTs), axonopathy) and neuroinflammation (microgliosis, astrocytosis) appeared in both WKY and SHR transgenic rats. Although identical levels of transgene expression in both lines were present, terminally-staged WKY transgenic rats displayed significantly lower final NFT loads than their SHR transgenic counterparts. Interestingly, microglial responses showed a striking difference between transgenic lines. Only 1.6% of microglia in SHR transgenic rats expressed MHCII in spite of having a robust phagocytic phenotype, whereas in WKY transgenic rats, 23.2% of microglia expressed MHCII despite displaying a considerably lower extent of transformation into phagocytic phenotype.</p> <p>Conclusions</p> <p>These results show that the immune response represents a pivotal and genetically variable modifying factor that is able to influence vulnerability to neurodegeneration. Therefore, targeted immunomodulation could represent a prospective therapeutic approach to Alzheimer's disease.</p> |
| first_indexed | 2024-12-14T19:59:22Z |
| format | Article |
| id | doaj.art-e2dcecd4b1a94ef287a0d2dfeea44de6 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-14T19:59:22Z |
| publishDate | 2010-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e2dcecd4b1a94ef287a0d2dfeea44de62022-12-21T22:49:12ZengBMCJournal of Neuroinflammation1742-20942010-10-01716410.1186/1742-2094-7-64Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's diseaseKovacech BranislavNovak PetrZilka NorbertStozicka ZuzanaBugos OndrejNovak Michal<p>Abstract</p> <p>Background</p> <p>Numerous epidemiological studies demonstrate that genetic background modifies the onset and the progression of Alzheimer's disease and related neurodegenerative disorders. The efficacious influence of genetic background on the disease pathway of amyloid beta has been meticulously described in rodent models. Since the impact of genetic modifiers on the neurodegenerative and neuroinflammatory cascade induced by misfolded tau protein is yet to be elucidated, we have addressed the issue by using transgenic lines expressing the same human truncated tau protein in either spontaneously hypertensive rat (SHR) or Wistar-Kyoto (WKY) genetic background.</p> <p>Methods</p> <p>Brains of WKY and SHR transgenic rats in the terminal stage of phenotype and their age-matched non-transgenic littermates were examined by means of immunohistochemistry and unbiased stereology. Basic measures of tau-induced neurodegeneration (load of neurofibrillary tangles) and neuroinflammation (number of Iba1-positive microglia, their activated morphology, and numbers of microglia immunoreactive for MHCII and astrocytes immunoreactive for GFAP) were quantified with an optical fractionator in brain areas affected by neurofibrillary pathology (pons, medulla oblongata). The stereological data were evaluated using two-way ANOVA and Student's t-test.</p> <p>Results</p> <p>Tau neurodegeneration (neurofibrillary tangles (NFTs), axonopathy) and neuroinflammation (microgliosis, astrocytosis) appeared in both WKY and SHR transgenic rats. Although identical levels of transgene expression in both lines were present, terminally-staged WKY transgenic rats displayed significantly lower final NFT loads than their SHR transgenic counterparts. Interestingly, microglial responses showed a striking difference between transgenic lines. Only 1.6% of microglia in SHR transgenic rats expressed MHCII in spite of having a robust phagocytic phenotype, whereas in WKY transgenic rats, 23.2% of microglia expressed MHCII despite displaying a considerably lower extent of transformation into phagocytic phenotype.</p> <p>Conclusions</p> <p>These results show that the immune response represents a pivotal and genetically variable modifying factor that is able to influence vulnerability to neurodegeneration. Therefore, targeted immunomodulation could represent a prospective therapeutic approach to Alzheimer's disease.</p>http://www.jneuroinflammation.com/content/7/1/64 |
| spellingShingle | Kovacech Branislav Novak Petr Zilka Norbert Stozicka Zuzana Bugos Ondrej Novak Michal Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease Journal of Neuroinflammation |
| title | Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease |
| title_full | Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease |
| title_fullStr | Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease |
| title_full_unstemmed | Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease |
| title_short | Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease |
| title_sort | genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy implication for immunomodulatory approach to alzheimer s disease |
| url | http://www.jneuroinflammation.com/content/7/1/64 |
| work_keys_str_mv | AT kovacechbranislav geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease AT novakpetr geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease AT zilkanorbert geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease AT stozickazuzana geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease AT bugosondrej geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease AT novakmichal geneticbackgroundmodifiesneurodegenerationandneuroinflammationdrivenbymisfoldedhumantauproteininratmodeloftauopathyimplicationforimmunomodulatoryapproachtoalzheimersdisease |