Research ArticleNEUROSCIENCE

A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease

+ See all authors and affiliations

Science Advances  10 Aug 2016:
Vol. 2, no. 8, e1600947
DOI: 10.1126/sciadv.1600947
  • Fig. 1 Tissue-specific transcriptional analysis of a subset of aggregation-prone proteins specific to AD.

    (A) For a given gene, we define a Δ score by the normalized differential expression between the brain regions under scrutiny and all non-Braak regions (see Methods). (B) Box plot of ΔBI–III (the Δ score for Braak regions I to III) for the whole proteome and the proteins that coaggregate with Aβ and tau in plaques and tangles. Aβ and tau are shown as square points in their respective distribution. ***P < 0.001; the statistical significance of the difference between the distributions of the coaggregators and that of the proteome was calculated using Mann-Whitney U test with Benjamini-Hochberg multiple hypothesis testing correction (50).

  • Fig. 2 In vulnerable tissues in healthy brains, the expression patterns of specific molecular chaperones and posttranslational modifiers predispose the aggregation of Aβ and tau.

    Proteins known to promote Aβ and tau aggregation (termed “promoters”) are shown within ellipses, and proteins known to protect against it (termed “protectors”) are shown within rectangular boxes (table S4). Proteins whose roles in Aβ and tau aggregation are ambiguous in the literature are shown without frames and not considered in further analysis. ΔBI–III scores are color-coded according to the legend in the lower left corner. Error bars in the plot represent a 95% confidence interval on the mean (X symbol) calculated with 105 bootstrap cycles, ***P < 0.001 calculated with a two-tailed t test (49).

  • Fig. 3 In healthy tissues, a protein homeostasis expression signature associated with Aβ and tau aggregation recapitulates the progression of AD well before the onset of the disease.

    (A) Tissues are colored according to the mean Δ score for expression in healthy brains of the aggregation modulators (protectors and promoters) of Aβ and tau aggregation (left) and to the Braak staging (right) (tables S4 to S6). The mean Δ score for aggregation modulator is calculated as the difference between the mean Δ scores for aggregation promoters and protectors in the region under scrutiny. (B) Box plot of the mean Δ scores for aggregation modulators [as calculated in (A)] in perfect-match tissues (see Methods) affected at progressive Braak stages (x axis). *****P < 0.00001; P values were calculated with Mann-Whitney U test with Benjamini-Hochberg multiple hypothesis testing correction (50). NB, non-Braak.

  • Fig. 4 Distributions of ΔBI–III scores for selected KEGG pathways.

    Box plots of the ΔBI–III score distributions for each pathway category (x axis) in the context of the whole proteome. “All pathways” is the distribution of the ΔBI–III scores of all proteins in the human proteome with at least one KEGG pathway assigned. Boxes represent the first and third quartiles of the distribution, whiskers represent the 1.5 interquartile range, and notches are the standard errors on the median calculated with 104 bootstrap cycles. Significance values (**P < 0.01 and *****P < 0.00001) report the statistical significance of the difference with the first box plot (All pathways) calculated using Mann-Whitney U test with Benjamini-Hochberg multiple hypothesis testing correction (50).

  • Fig. 5 Expression of different components of Aβ and tau homeostasis in specific brain cell types.

    For different brain cell types, including neurons, astrocytes, microglia, and endothelial cells, we calculated the relative mRNA expression levels (40), as measured by the Embedded Image score (see Methods), of genes corresponding to Aβ and tau, and the corresponding aggregation protectors and promoters. For each gene set in neurons, the significance of the difference with the expression distribution for all other brain cell types in combination was calculated using Mann-Whitney U test with Benjamini-Hochberg multiple hypothesis testing correction (50); ***P < 0.001 and *****P < 0.00001.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/8/e1600947/DC1

    table S1. Mapping between Braak regions and Allen Brain Atlas regions.

    table S2. Δ Scores for the reference proteome.

    table S3. Proteins that aggregate in neurodegenerative disease.

    table S4. Modulators of Aβ and tau aggregation.

    table S5. Brain regions colored in Fig. 3A.

    table S6. Aggregation modulator Δ scores for all Braak stages.

    table S7. KEGG pathways.

    table S8. Data sources.

    fig. S1. Schematic illustration of the calculation process of the Δ scores.

    fig. S2. Analysis of the average correlation between mRNA and protein levels.

    fig. S3. Analysis of ΔBI–III scores of random sets of genes.

    fig. S4. ΔSNPC scores corresponding to aggregation-prone protein sets characteristic of PD.

    fig. S5. Distributions of Δ scores for tissues affected at different Braak stages.

    fig. S6. Proteome-based Δ scores calculated using mice data for tissues affected at different Braak stages.

    fig. S7. ΔBI–III Scores for neurodegenerative disease–specific aggregation modulator sets.

  • Supplementary Materials

    This PDF file includes:

    • Legends for tables S1 to S8
    • fig. S1. Schematic illustration of the calculation process of the Δ scores.
    • fig. S2. Analysis of the average correlation between mRNA and protein levels.
    • fig. S3. Analysis of ΔBI–III scores of random sets of genes.
    • fig. S4. ΔSNPC scores corresponding to aggregation-prone protein sets characteristic of PD.
    • fig. S5. Distributions of Δ scores for tissues affected at different Braak stages.
    • fig. S6. Proteome-based Δ scores calculated using mice data for tissues affected at different Braak stages.
    • fig. S7. ΔBI–III Scores for neurodegenerative disease–specific aggregation modulator sets.

    Download PDF

    Other Supplementary Material for this manuscript includes the following:

    • table S1 (Microsoft Excel format). Mapping between Braak regions and Allen Brain Atlas regions.
    • table S2 (Microsoft Excel format). Δ Scores for the reference proteome.
    • table S3 (Microsoft Excel format). Proteins that aggregate in neurodegenerative disease.
    • table S4 (Microsoft Excel format). Modulators of Aβ and tau aggregation.
    • table S5 (Microsoft Excel format). Brain regions colored in Fig. 3A.
    • table S6 (Microsoft Excel format). Aggregation modulator Δ scores for all Braak stages.
    • table S7 (Microsoft Excel format). KEGG pathways.
    • table S8 (Microsoft Excel format). Data sources.

    Download tables S1 to S8

    Files in this Data Supplement: