Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Yan, Shi, Jianhua, Chu, Dandan, Hu, Wen, Guan, Zongyu, Gong, Cheng-Xin, Iqbal, Khalid, Liu, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810298/
https://www.ncbi.nlm.nih.gov/pubmed/29472853
http://dx.doi.org/10.3389/fnagi.2018.00027
_version_ 1783299730343723008
author Zhou, Yan
Shi, Jianhua
Chu, Dandan
Hu, Wen
Guan, Zongyu
Gong, Cheng-Xin
Iqbal, Khalid
Liu, Fei
author_facet Zhou, Yan
Shi, Jianhua
Chu, Dandan
Hu, Wen
Guan, Zongyu
Gong, Cheng-Xin
Iqbal, Khalid
Liu, Fei
author_sort Zhou, Yan
collection PubMed
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.
format Online
Article
Text
id pubmed-5810298
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-58102982018-02-22 Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease Zhou, Yan Shi, Jianhua Chu, Dandan Hu, Wen Guan, Zongyu Gong, Cheng-Xin Iqbal, Khalid Liu, Fei Front Aging Neurosci Neuroscience 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. Frontiers Media S.A. 2018-02-06 /pmc/articles/PMC5810298/ /pubmed/29472853 http://dx.doi.org/10.3389/fnagi.2018.00027 Text en Copyright © 2018 Zhou, Shi, Chu, Hu, Guan, Gong, Iqbal and Liu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Zhou, Yan
Shi, Jianhua
Chu, Dandan
Hu, Wen
Guan, Zongyu
Gong, Cheng-Xin
Iqbal, Khalid
Liu, Fei
Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease
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 Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810298/
https://www.ncbi.nlm.nih.gov/pubmed/29472853
http://dx.doi.org/10.3389/fnagi.2018.00027
work_keys_str_mv AT zhouyan relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT shijianhua relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT chudandan relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT huwen relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT guanzongyu relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT gongchengxin relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT iqbalkhalid relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease
AT liufei relevanceofphosphorylationandtruncationoftautotheetiopathogenesisofalzheimersdisease