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. 2018 Feb 6:10:27.
doi: 10.3389/fnagi.2018.00027. eCollection 2018.

Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer's Disease

Yan Zhou  1   2   3 , Jianhua Shi  1   2 , Dandan Chu  1 , Wen Hu  1   2 , Zongyu Guan  1 , Cheng-Xin Gong  2 , Khalid Iqbal  2 , Fei Liu  1   2
Affiliations

Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer's Disease

Yan Zhou et al. Front Aging Neurosci. .

Abstract

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.

Keywords: Alzheimer’s disease; hyperphosphorylation; tau; tau pathogenesis; truncation.

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Figures

Figure 1
Figure 1
High-molecular weight tau (HMW-tau) is selectively present in Alzheimer’s disease (AD) brain. (A) Frontal cortical homogenates from 17 control and 17 AD cases were analyzed by western blots developed with a pan-tau antibody, 92e. (B) Blots were analyzed by densitometry. The levels of total tau, HMW-tau, low molecular tau (LMW-tau), and ratio of the HMW-tau/LMW-tau are presented as scattered dots with mean ± SD. **p < 0.01; ****p < 0.0001.
Figure 2
Figure 2
Both HMW-tau and LMW-tau are selectively hyperphosphorylated in AD brain. (A) AD and control human brain homogenates were analyzed by western blots developed with the indicated site-specific and phosphorylation dependent anti-tau antibodies. (B,C) Blots were analyzed by densitometry. The levels of hyperphosphorylated HMW-tau (B) and LMW-tau (C) are shown as scattered dots with mean ± SD. **p < 0.01; ***p < 0.001; ****p < 0.0001.
Figure 3
Figure 3
Tau unphosphorylated at Ser46 and Ser198/199/202 is not present in the HMW-tau species. (A) The levels of tau unphosphorylated at Ser46 and Ser198/199/202 in human brain homogenates were determined by western blots. (B) Blots were analyzed by densitometry. Quantification is presented as scattered dots with mean ± SD. *p < 0.05; ***p < 0.001.
Figure 4
Figure 4
HWM-tau is mainly truncated at the N-terminus. (A) Schematic diagram of the epitopes of tau antibodies used in the present study. (B,C) Western blots of brain homogenates from 10 control and 10 AD cases developed with six tau antibodies indicated under each blot and analyzed by densitometry. The levels of HMW-tau and LMW-tau and the ratio of HMW-tau/LMW-tau are presented as scattered dots with mean ± SD. *p < 0.05, ***p < 0.001, ****p < 0.0001. (D) The ratios of HMW-tau/LMW-tau detected by individual tau antibodies were present as scattered dots with mean ± SD. The levels detected by all antibodies are significantly different, except between by HT-7 and by RD4 by repeated measures analysis of variance (ANOVA) followed by Tukey’s multiple comparisons test. (E) The mean ratio of HWM-tau/LMW-tau detected by each antibody was plotted against the medium a.a. of corresponding epitope. Spearman correlation analysis was performed by including antibodies 43D, HT7, RD4, RD3 and Tau46, but not Tau46.1, which is marked with a circle.
Figure 5
Figure 5
Tau truncated at D421 does not associate with HMW-tau in AD brains. (A) Level of tauD421 was determined by western blots developed with Tau-C3 antibody using short or long exposures. (B) Blots were quantified by densitometry. The levels of HMW-tauD421 and LMW-tauD421 and the ratio of HMW-tauD421/LMW-tauD421 are shown as scattered dots with mean ± SD. *p < 0.05.
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