Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease
Microtubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer’s disease (AD) and related tauopathies. Hyperphosphorylation and truncation of t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnagi.2018.00027/full |
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| author | Yan Zhou Yan Zhou Yan Zhou Jianhua Shi Jianhua Shi Dandan Chu Wen Hu Wen Hu Zongyu Guan Cheng-Xin Gong Khalid Iqbal Fei Liu Fei Liu |
| author_facet | Yan Zhou Yan Zhou Yan Zhou Jianhua Shi Jianhua Shi Dandan Chu Wen Hu Wen Hu Zongyu Guan Cheng-Xin Gong Khalid Iqbal Fei Liu Fei Liu |
| author_sort | Yan Zhou |
| collection | DOAJ |
| description | Microtubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer’s disease (AD) and related tauopathies. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain are not very clear. In the present study we investigated the association of phosphorylation and truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by western blots. We found that tau from AD brain appears as a smear from low molecular weight (LMW) to HMW tau species in western blots developed with pan-tau antibodies. Similar level of LMW-tau was found in AD and control brains, whereas HMW-tau was found in AD brain only. HMW-tau was hyperphosphorylated at multiple sites and not unphosphorylated at Ser46 or Ser198/199/202. HMW-tau was weakly labeled by tau antibodies 43D against a.a. 6–18 and HT7 against a.a. 159–163 of tau, whereas, the C-terminal antibodies, tau46 and tau46.1, strongly labeled HMW-tau. The ratio of HMW-tau/LMW-tau detected by tau antibodies increased as the epitope of the tau antibodies ranges from N-terminal to C-terminal. The level of tau truncated at Asp421 was increased in AD brain, but was poorly associated with the HMW-tau. These findings suggest that tau pathogenesis involves both hyperphosphorylation and dominantly N-terminal truncation of tau in AD. |
| first_indexed | 2024-12-23T21:17:03Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-23T21:17:03Z |
| publishDate | 2018-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-a71c4145ae0342068de2075fa070cdc52022-12-21T17:30:52ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652018-02-011010.3389/fnagi.2018.00027343987Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s DiseaseYan Zhou0Yan Zhou1Yan Zhou2Jianhua Shi3Jianhua Shi4Dandan Chu5Wen Hu6Wen Hu7Zongyu Guan8Cheng-Xin Gong9Khalid Iqbal10Fei Liu11Fei Liu12Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesDepartment of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaDepartment of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United StatesMicrotubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer’s disease (AD) and related tauopathies. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain are not very clear. In the present study we investigated the association of phosphorylation and truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by western blots. We found that tau from AD brain appears as a smear from low molecular weight (LMW) to HMW tau species in western blots developed with pan-tau antibodies. Similar level of LMW-tau was found in AD and control brains, whereas HMW-tau was found in AD brain only. HMW-tau was hyperphosphorylated at multiple sites and not unphosphorylated at Ser46 or Ser198/199/202. HMW-tau was weakly labeled by tau antibodies 43D against a.a. 6–18 and HT7 against a.a. 159–163 of tau, whereas, the C-terminal antibodies, tau46 and tau46.1, strongly labeled HMW-tau. The ratio of HMW-tau/LMW-tau detected by tau antibodies increased as the epitope of the tau antibodies ranges from N-terminal to C-terminal. The level of tau truncated at Asp421 was increased in AD brain, but was poorly associated with the HMW-tau. These findings suggest that tau pathogenesis involves both hyperphosphorylation and dominantly N-terminal truncation of tau in AD.http://journal.frontiersin.org/article/10.3389/fnagi.2018.00027/fullAlzheimer’s diseasetauhyperphosphorylationtruncationtau pathogenesis |
| spellingShingle | Yan Zhou Yan Zhou Yan Zhou Jianhua Shi Jianhua Shi Dandan Chu Wen Hu Wen Hu Zongyu Guan Cheng-Xin Gong Khalid Iqbal Fei Liu Fei Liu Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease Frontiers in Aging Neuroscience Alzheimer’s disease tau hyperphosphorylation truncation tau pathogenesis |
| title | Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease |
| title_full | Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease |
| title_fullStr | Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease |
| title_full_unstemmed | Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease |
| title_short | Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease |
| title_sort | relevance of phosphorylation and truncation of tau to the etiopathogenesis of alzheimer s disease |
| topic | Alzheimer’s disease tau hyperphosphorylation truncation tau pathogenesis |
| url | http://journal.frontiersin.org/article/10.3389/fnagi.2018.00027/full |
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