Research ArticleGLYCOBIOLOGY

Interplay between protein glycosylation pathways in Alzheimer’s disease

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Science Advances  15 Sep 2017:
Vol. 3, no. 9, e1601576
DOI: 10.1126/sciadv.1601576
  • Fig. 1 Alterations of protein O-GlcNAcylation in AD.

    Protein O-GlcNAcylation levels were measured by ELISA using an O-β-GlcNAc–specific monoclonal antibody (CTD 110.6). Results of soluble cytoplasmic fraction (A) (n = 7 per group), membrane fraction (B) (n = 7 per group), and serum (C) (n = 14 to 15 per group) are presented as ratios, normalized to healthy controls. P values were calculated by Student’s t test. **P < 0.05 and ***P < 0.001.

  • Fig. 2 Global glycosylation alterations in AD.

    Glycan levels were measured by quantitative PAS staining, which detects both N- and O-glycosylation. Results of the soluble cytoplasmic fraction (A) (n = 7 per group), membrane fraction (B) (n = 7 per group), and serum (C) (n = 14 to 15 per group) are presented as ratios, normalized to healthy controls. P values were calculated by Student’s t test. **P < 0.05 and ***P < 0.001.

  • Fig. 3 Lectin array assay of serum samples from AD (red), MCI (green) patients, and healthy controls (blue) (n = 10).

    P values were calculated by analysis of variance (ANOVA) for normal distribution or by Kruskal-Wallis test for non-normal distribution. *P < 0.1, **P < 0.05, and ***P < 0.001.

  • Table 2 Human brain tissue of AD and control cases used in this study.

    PMD, postmortem delay; N/A, not applicable.

    Case numberGenderPMD (hours)Age at
    death (years)
    Braak stageBrain bank identifier number
    Con 1F2280IIBBN_20040
    Con 2M5384N/ABBN_18816
    Con 3M4590N/ABBN_14408
    Con 4M2665IBBN_10992
    Con 5M2567IBBN_10208
    Con 6M2363N/ABBN_10209
    Con 7F992IIBBN_10250
    Mean ± SD29 ± 14.977.28 ± 12.2
    AD 1F4278VIBBN_19593
    AD 2F2074VIBBN_18818
    AD 3M3388VBBN_16191
    AD 4M2776VIBBN_15597
    AD 5M2267VIBBN_16202
    AD 6F1570V–VIBBN_15201
    AD 7M2478VBBN_11075
    Mean ± SD26.14 ± 9.075.86 ± 6.7
  • Table 3 Human serum samples of AD, MCI, and control cases used in this study.
    Case numberGenderPMD (hours)Age at
    death (years)
    Braak stageAmyloid*NBB identifier number
    Con 1F3771B2009-022
    Con 2F6.5781A2000-032
    Con 3M7781A2000-049
    Con 4F4.5811O2011-028
    Con 5F4.5782A2012-059
    Con 6F5.5792B1999-052
    Con 7M6792A2012-070
    Con 8M8812O2007-082
    Con 9M13.5822A2000-030
    Con 10M10824B2003-084
    Con 11F4.75781A2001-028
    Con 12M5.75831B2011-017
    Con 13F7.25762O2011-072
    Con 14M6.5792A2012-104
    Mean ± SD6.85 ± 3.179. 2 ± 1.8
    AD 1M8745C2011-115
    AD 2M5795C2001-092
    AD 3F4795C2002-085
    AD 4M4.5855C2001-044
    AD 5M5855C2001-063
    AD 6F5.5736C2011-053
    AD 7F5786C1998-142
    AD 8M10786C2000-001
    AD 9F5816C2007-059
    AD 10F5.5826C2010-054
    AD 11F5.5766C1999-140
    AD 12M4.5806C2000-066
    AD 13M4.5775C2007-078
    AD 14M6.25865C2010-016
    Mean ± SD6.9 ± 3.379.6 ± 4.2
    MCI 1M10721B2001-075
    MCI 2M5791B2006-033
    MCI 3F4821B2001-131
    MCI 4F7821A2008-104
    MCI 5F6762O2005-058
    MCI 6M4.5792A2008-048
    MCI 7M6703B2013-030
    MCI 8F4763B2008-015
    MCI 9M5823B2008-016
    MCI 10F5833B2007-039
    MCI 11F5.5833B2007-061
    MCI 12F5.5853C1999-074
    MCI 13F4.5852C2001-061
    MCI 14F4.5891C2006-053
    MCI 15M6.5793A2009-064
    Mean ± SD5.5 ± 180.1 ± 4.6

    *Amyloid stage (59): stage A, amyloid deposits mainly found in the basal portions of the frontal, temporal, and occipital lobes; stage B, all isocortical association areas affected, whereas the hippocampal formation is only mildly involved, and the primary sensory, motor, and visual cortices are devoid of amyloid; and stage C, deposition of amyloid in these primary isocortical areas and, in some cases, the appearance of amyloid deposits in the molecular layer of the cerebellum and subcortical nuclei, such as striatum, thalamus, hypothalamus, subthalamic nucleus, and red nucleus.

    • Table 4 Human frontal cortex samples of tauopathy and control cases used in this study.
      Case numberGenderPMD (hours)Age at
      death (years)
      MRC identifier number
      Con 1F4877BBN_3378
      Con 2M14478BBN_5761
      Con 3F4181BBN_3447
      Con 4F3987BBN_3454
      Con 5F92.553BBN_6067
      Con 6M9284BBN_6071
      Con 7M9885BBN_20005
      Con 8M69.584BBN_20006
      Mean ± SD78.6 ± 10.91
      CBD 1MN/A75BBN_3326
      CBD 2F2077BBN_3335
      CBD 3MN/A65BBN_3346
      CBD 4M4873BBN_3381
      CBD 5M40.570BBN_3427
      CBD 6M68.580BBN_3431
      CBD 7M5390BBN_3450
      CBD 8M2879BBN_3474
      CBD 9M11964BBN_6077
      CBD 10F8171BBN_6082
      Mean ± SD74.4 ± 7.69
      PSP 1FN/AN/ABBN_3065
      PSP 2FN/A60BBN_3083
      PSP 3M2576BBN_3462
      PSP 4M50.580BBN_10262
      PSP 5F43.580BBN_21011
      Mean ± SD74 ± 9.52
      FTLD-tau Picks 1FN/A60BBN_3041
      FTLD-tau Picks 2MN/A56BBN_3053
      FTLD-tau Picks 3FN/A84BBN_3100
      FTLD-tau Picks 4FN/A58BBN_3182
      FTLD-tau Picks 5MN/A77BBN_3222
      FTLD-tau Picks 6MN/A69BBN_3288
      FTLD-tau Picks 7M10275BBN_3433
      FTLD-tau Picks 8M12569BBN_6069
      Mean ± SD68.5 ± 9.96
      FTLD-tau MAPT 1FN/A58BBN_5696
      FTLD-tau MAPT 2MN/A55BBN_5699
      FTLD-tau MAPT 3MN/A70BBN_5710
      FTLD-tau MAPT 4FN/A65BBN_5717
      FTLD-tau MAPT 5MN/A53BBN_5733
      FTLD-tau MAPT 6F3660BBN_5744
      FTLD-tau MAPT 7F9663BBN_5760
      FTLD-tau MAPT 8F4858BBN_5763
      FTLD-tau MAPT 9F5363BBN_6081
      Mean ± SD60.5 ± 5.27
    • Table 1 Interplay between levels of global protein O-GlcNAcylation and N-/O-glycosylation in brain and serum samples of AD patients.

      cx, cortex; ↓, down-regulation; ↑, up-regulation; −, no significant change; Sup, supernatant (this fraction is enriched with cytoplasmic proteins); Pellet (this fraction is enriched with membrane proteins).

      RegionFrontal cxHippocampusParietal cxTemporal cxSerum
      TypeSupPelletSupPelletSupPelletSupPelletADMCI
      O-GlcNAc
      N-/O-glycosylation

    Supplementary Materials

    • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/9/e1601576/DC1

      fig. S1. Age distribution box plot of donors of sample of brains and serum.

      fig. S2. Verification of the identity of the cytoplasmic and membrane fractions of two AD patients and two healthy counterparts.

      fig. S3. Calibration of quantitative PAS staining.

      fig. S4. Alterations of glycosylation in the soluble cytoplasmic fraction of the frontal cortex of tauopathy patients.

      fig. S5. List and structure of glycans depicted in the LecChip.

    • Supplementary Materials

      This PDF file includes:

      • fig. S1. Age distribution box plot of donors of sample of brains and serum.
      • fig. S2. Verification of the identity of the cytoplasmic and membrane fractions of two AD patients and two healthy counterparts.
      • fig. S3. Calibration of quantitative PAS staining.
      • fig. S4. Alterations of glycosylation in the soluble cytoplasmic fraction of the frontal cortex of tauopathy patients.
      • fig. S5. List and structure of glycans depicted in the LecChip.

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