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Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice

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Science  18 Nov 2016:
Vol. 354, Issue 6314, pp. 904-908
DOI: 10.1126/science.aah6205

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  • A supporting evidence on the aetiology of Alzheimer’s disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Sirui Yan, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Xingjian Wang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    We previously proposed that insoluble and rigid calcium salts such as calcium oxalate underlie Alzheimer’s disease.(1-3) As a proof, the majority of people experiencing constipation develop Alzheimer’s disease.(4-5) The insoluble and rigid salts in the body may confer the symptom of constipation. This phenomenon warrants further investigations.

    Xingjian Wang, 1,2 Sirui Yan, 1,2 Qiuyun Liu1*
    1State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Lab of Microbial Metabolic Engineering and Synthetic Biology, School of Life Sciences, Sun Yat-sen University, China.
    2Equal contributions.
    *Corresponding author: lsslqy@mail.sysu.edu.cn (Q. Liu)
    References
    1. J Zou, et al. Science 2017, http://science.sciencemag.org/content/354/6314/904/tab-e-letters
    2. Y Wan et al. Eur J Prev Cardiol 2018; 25(8): 881-882.
    3. J Qi et al. Eur J Prev Cardiol 2018; 25(8): 883-884.
    4. DK Kiely, et al. Int J Geriatr Psychiatry. 2000; 15(11):1013-1020
    5. M Coggrave, et al. Cochrane Database Syst Rev. 2014; (1):CD002115. doi: 10.1002/14651858.CD002115.

    Competing Interests: None declared.
  • Removal of valine- and glycine-rich peptides from food-grade protein hydrolysate for relief of Alzheimer’s disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Xiaoyi Hu, Researcher, Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA.
      • Fan Yang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Sirui Yan, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    The glycine contents in the prion proteins of Bos Taurus and Homo sapiens are near or about 20% (GenBank accession number ABJ52648.1, ABW89582.1 and AAA60182.1). Valine and glycine are overrepresented in some risk factors of heart disease and Alzheimer’s disease (1-2), and are proposed to possess potent affinities to divalent cations as the long C=O bond lengths allow robust secondary chemical bonding on their carbonyl oxygen atoms.(3) Calcium oxalate was postulated to be one of the causative factors of Alzheimer’s disease.(1-2) As carbohydrate-based diet does not give rise to essential amino acids, a starch-based diet may reduce the cellular levels of the risk factors of the disorder.(4) In situations not suitable for a carbohydrate-based diet, the protein hydrolysate devoid of the two amino acids may be adopted as an alternative food source. Carefully designed affinity resin harboring defined divalent cations binds valine- and glycine-rich peptides at acidic pH, without retaining the beneficial acidic amino acids. The flow-through of the column contains protein hydrolysate suitable for intake by the patients after further purifications.

    Fan Yang, 1,2 Xiaoyi Hu, 1,2 Sirui Yan, 1,2 Qiuyun Liu1*
    1State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Lab of Microbial Metabolic Engineering and Synthetic Biology, School of Life Sciences, Sun Yat-sen University, China.
    2Columbi...

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    Competing Interests: None declared.
  • From Sickle-cell anemia to Alzheimer’s disease. What do they have in common?
    • Qiuyun Liu, Professor, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, China
    • Other Contributors:
      • Danling Dai, Student, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
      • Zi-Wei Ye, Student, School of Biological Sciences, the University of Hong Kong, Hong Kong.
      • Xi Luo, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Sickle-cell anemia (SCA) patients display defect in erythrocytes. A glutamic acid replacement by valine in hemoglobin causes deformity of cell form (1), leading to a rigid, sickle-like shape in homozygotes. Other manifestations include anemia, swelling in the hands and feet, etc. The rigid shape of red blood cells may be resulted from replacement from valine residue, whose two gamma methyl groups allow hyperconjugation and van der Waals interactions with carbonyl oxygen, consequently giving rise to potent cation affinities including calcium ions and formation of insoluble and rigid salts with organic acids and so on (2). The enrichment of this defect in the human population may be the consequences of evolutionary selections against malaria (1). The cell swelling observed with valine replacement has been proposed to be harnessed in crop yield enhancement (3). The genetic risk factors for Alzheimer’s disease possess high content of valine (2), which may share some common features with sickle-cell anemia.

    Danling Dai, 2 Zi-Wei Ye, 3 Xi Luo, 1 Qiuyun Liu, 1*
    1. State Key Laboratory of Biocontrol, Key Laboratory for Improved Variety Reproduction of Aquatic Economic Animals of Guangdong Province, Biotechnology Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
    2. Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
    3. School of Biological Sciences, the University of Hong Kong, Hong Kong.

    *Correspon...

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    Competing Interests: None declared.
  • RE: High-valine diets need to be restricted for Alzheimer’s disease patients
    • Qiuyun Liu, Professor, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, China.
    • Other Contributors:
      • Yunfan Shi, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Yulin Wan, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Shuying He, Senior Scientist, 450E 29th St, New York ,NY 10016

    The Genetic risk factors of Alzheimer’s disease such as APP, S182, STM-2 and ApoE

    proteins harbor between 7% and 10% valine with 2 gamma methyl groups, which

    enables hyperconjugation (1) and van der Waals interactions (2) with its carbonyl

    group, thus leading to strong cation bonding with carbonyl oxygen. To avoid the

    formation of insoluble salts between divalent cations and organic acids or other

    substances, valine-rich diets need to be restricted for Alzheimer’s disease patients.

    Calcium-rich diets also need to be avoided as they are likely to form insoluble and

    rigid salts, which may be damaging to cells. Diets rich in hydrogen bond donors and

    acceptors such as food of aquatic origin could help dissolve insoluble salts in human

    body and relieve the symptoms of Alzheimer’s disease.

    Yunfan Shi, 1 Yulin Wan, 1 Shuying He, 2 Qiuyun Liu, 1*

    1. State Key Laboratory of Biocontrol, Key Laboratory for Improved Variety

    Reproduction of Aquatic Economic Animals of Guangdong Province, Biotechnology

    Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou

    510275, China.

    2. 450E 29th St, New York, NY 10016 USA.

    *Correspondence author.

    E-mail address: lsslqy@mail.sysu.edu.cn (Q. Liu)

    REFERENCES

    1. J. Zou et al. Science, (2017);

    ...

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    Competing Interests: None declared.
  • RE: “Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice”
    • Qiuyun Liu, Superviser and writting/Professor, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China
    • Other Contributors:
      • Juntong Zou, Writting/Student, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China
      • Yanchao Zhou, Writting/Student, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China
      • Man Tang, Writting/Student, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China
      • Jianguo He, Writting/Professor, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China

    Phosphorylation of tau: A chemical perspective

    In their article “Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice” (18 November, 2016, p. 904), Ittner et al. described findings contradictory to previous reports. We believe a mechanism involving secondary chemical bonding could at least partly account for it. APP, S182, STM-2 and ApoE proteins harbor between 7% and 10% valine with 2 gamma methyl groups, which may enable hyperconjugation (1-2) and van der Waals interactions (3) with its carbonyl group. The chemical shift anisotropy of σ22 element of the tensor was a sign of the hydrogen bond strength with its carbonyl oxygen (4,5). The long bond length of the carbonyl carbon with oxygen of valine may be an indication of secondary bonding capacity between carbonyl oxygen and cations (4,6).
    Age related Alzheimer’s disease may occur in the wake of attenuated ATP productions and a fully functional Krebs cycle. The gradual buildup of organic acids might form insoluble salts with divalent cations which may disrupt cells. Numerous organic acids have modest median lethal doses on animals. Calcium phosphate is also insoluble and rigid, which explains the pathogenic role of tau phosphorylation in numerous reports. The phosphorylation of T205 may have abolished secondary chemical bonding between the hydroxyl oxygen of threonine and divalent cations, consequently reducing the formation of insoluble salts. Many amino acid mutations wi...

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    Competing Interests: None declared.

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