Phosphorylation of different tau sites during progression of Alzheimer’s disease
Abstract Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0557-6 |
| _version_ | 1828432958053154816 |
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| author | Joerg Neddens Magdalena Temmel Stefanie Flunkert Bianca Kerschbaumer Christina Hoeller Tina Loeffler Vera Niederkofler Guenther Daum Johannes Attems Birgit Hutter-Paier |
| author_facet | Joerg Neddens Magdalena Temmel Stefanie Flunkert Bianca Kerschbaumer Christina Hoeller Tina Loeffler Vera Niederkofler Guenther Daum Johannes Attems Birgit Hutter-Paier |
| author_sort | Joerg Neddens |
| collection | DOAJ |
| description | Abstract Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets. |
| first_indexed | 2024-12-10T18:27:33Z |
| format | Article |
| id | doaj.art-5e739ae9d8044eee9e537a57254e5932 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T18:27:33Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-5e739ae9d8044eee9e537a57254e59322022-12-22T01:38:01ZengBMCActa Neuropathologica Communications2051-59602018-06-016111510.1186/s40478-018-0557-6Phosphorylation of different tau sites during progression of Alzheimer’s diseaseJoerg Neddens0Magdalena Temmel1Stefanie Flunkert2Bianca Kerschbaumer3Christina Hoeller4Tina Loeffler5Vera Niederkofler6Guenther Daum7Johannes Attems8Birgit Hutter-Paier9QPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyQPS Austria GmbH, NeuropharmacologyInstitute for Biochemistry, Graz University of TechnologyInstitute of Neuroscience and Newcastle University Institute for Ageing Campus for Ageing and Vitality, Newcastle UniversityQPS Austria GmbH, NeuropharmacologyAbstract Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.http://link.springer.com/article/10.1186/s40478-018-0557-6Microtubule-associated protein tauPhosphorylationCingulateFrontalOccipital and temporal cortexTransentorhinal region |
| spellingShingle | Joerg Neddens Magdalena Temmel Stefanie Flunkert Bianca Kerschbaumer Christina Hoeller Tina Loeffler Vera Niederkofler Guenther Daum Johannes Attems Birgit Hutter-Paier Phosphorylation of different tau sites during progression of Alzheimer’s disease Acta Neuropathologica Communications Microtubule-associated protein tau Phosphorylation Cingulate Frontal Occipital and temporal cortex Transentorhinal region |
| title | Phosphorylation of different tau sites during progression of Alzheimer’s disease |
| title_full | Phosphorylation of different tau sites during progression of Alzheimer’s disease |
| title_fullStr | Phosphorylation of different tau sites during progression of Alzheimer’s disease |
| title_full_unstemmed | Phosphorylation of different tau sites during progression of Alzheimer’s disease |
| title_short | Phosphorylation of different tau sites during progression of Alzheimer’s disease |
| title_sort | phosphorylation of different tau sites during progression of alzheimer s disease |
| topic | Microtubule-associated protein tau Phosphorylation Cingulate Frontal Occipital and temporal cortex Transentorhinal region |
| url | http://link.springer.com/article/10.1186/s40478-018-0557-6 |
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