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. 2020 Sep 16:11:575953.
doi: 10.3389/fneur.2020.575953. eCollection 2020.

Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease

Annie G Bryant  1 , Miwei Hu  1 , Becky C Carlyle  1 , Steven E Arnold  1 , Matthew P Frosch  1   2 , Sudeshna Das  1 , Bradley T Hyman  1 , Rachel E Bennett  1
Affiliations

Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease

Annie G Bryant et al. Front Neurol. .

Abstract

Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis and progression of AD, in part through endothelial dysfunction. Based on findings in animal models that tau pathology induces vascular abnormalities and cellular senescence, we hypothesized that tau pathology in the human AD brain leads to vascular senescence. To explore this hypothesis, we isolated intact microvessels from the dorsolateral prefrontal cortex (PFC, BA9) from 16 subjects with advanced Braak stages (Braak V/VI, B3) and 12 control subjects (Braak 0/I/II, B1), and quantified expression of 42 genes associated with senescence, cell adhesion, and various endothelial cell functions. Genes associated with endothelial senescence and leukocyte adhesion, including SERPINE1 (PAI-1), CXCL8 (IL8), CXCL1, CXCL2, ICAM-2, and TIE1, were significantly upregulated in B3 microvessels after adjusting for sex and cerebrovascular pathology. In particular, the senescence-associated secretory phenotype genes SERPINE1 and CXCL8 were upregulated by more than 2-fold in B3 microvessels after adjusting for sex, cerebrovascular pathology, and age at death. Protein quantification data from longitudinal plasma samples for a subset of 13 (n = 9 B3, n = 4 B1) subjects showed no significant differences in plasma senescence or adhesion-associated protein levels, suggesting that these changes were not associated with systemic vascular alterations. Future investigations of senescence biomarkers in both the peripheral and cortical vasculature could further elucidate links between tau pathology and vascular changes in human AD.

Keywords: Alzheimer's disease; endothelial senescence; gene expression; neurofibrillary tangles; plasma biomarkers; tau pathology; vascular dysfunction.

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Figures

Figure 1
Figure 1
Senescence-associated genes form a fold change hotspot in prefrontal cortex microvessels isolated from high-Braak (B3) vs. low-Braak (B1) samples. Differential gene expression between microvessels isolated from B3 vs. B1 samples, grouped by hypothesis-driven gene function groups. Values reflect log2-transformed fold change values relative to the B1 subject mean expression per gene. Relative quantification was performed such that the mean of B1 fold changes is zero for each gene. For this visualization, missing data were imputed with the ABC-Braak group mean fold change for the gene.
Figure 2
Figure 2
Senescence- and adhesion-associated genes are significantly upregulated in prefrontal cortex microvessels isolated from B3 vs. B1 subjects. (A) Senescence-associated genes are significantly upregulated in B3 cerebral microvessels with a log2 fold change of 1.323; Welch's unpaired t-test, p = 0.0030 (BH-corrected FDR 0.0208), 95% CI for B3 log2 fold change: 0.5019, 2.1442. Cell adhesion genes are also significantly upregulated with a log2 fold change of 0.953; Welch's unpaired t-test, p = 0.0161 (BH-FDR 0.0562), 95% CI for B3 log2 fold change: 0.1945, 1.7123. (B) Volcano plot showing t-test results. Dashed vertical lines denote magnitudes of 2-fold change and the dashed horizontal line denotes the cutoff for p < 0.05. (C) Stepwise multiple regression models were applied to senescence-associated and cell adhesion functional groups to measure the association between Braak stage and functional group average fold change. The first row indicates the independent variables upon which the average fold change was regressed per model for each functional group. Within each model, the ABC-Braak term regression coefficient (β1), p-value, and BH-FDR are reported. Significant ABC-Braak β1 terms are denoted with **p < 0.01, *p < 0.05.
Figure 3
Figure 3
Eleven genes related to senescence, adhesion, endothelial cell function, and VEGF/NOTCH pathways are significantly upregulated in PFC capillaries from B3 samples relative to B1 samples. (A) 11 genes show significant upregulation in B3 vs. B1 microvessels. Welch's unpaired t-test results are shown: **p < 0.01, *p < 0.05, all BH-FDR < 0.2. Plots are shaded by hypothesis-driven functional group. (B) Stepwise multiple regression models were applied to each of the 6 most-consistently upregulated genes to measure the association between Braak change and log2 fold change, adjusting for potential confounders. The first row indicates the independent variables upon which the log2 fold change was regressed per model for each gene. Within each model, the ABC-Braak term regression coefficient (β1), p-value, and BH-FDR are reported. Significant ABC-Braak β1 terms are marked in bold with **p < 0.01, *p < 0.05.
Figure 4
Figure 4
MAdCAM-1 upregulation demonstrates interaction between Braak stage and presence of cerebrovascular pathology. ANOVA with interaction demonstrated significant interaction between a high Braak score (B3) and presence of cerebrovascular pathology in MAdCAM1 expression out of all 40 genes quantified. Data shown in the boxplot reflect Tukey's HSD post-hoc test results, with **p < 0.01, *p < 0.05. A total of 6 samples did not have detectable expression, with an even distribution of missing data across the four groups. The number of samples with detected MAdCAM-1 expression per group are indicated at the bottom of the boxes.
Figure 5
Figure 5
Principal component composite gene scores in B3 vs. B1 microvessels show variance driven by senescence and adhesion genes. (A) PC loadings are plotted for each gene in PC1 (x-axis) and PC2 (y-axis). The rightmost shaded region contains the genes considered to be top contributors to PC1, with their percent contribution at least one standard deviation above the mean contribution. Genes immediately adjacent to this top contributor subset are also labeled. Point and text colors correspond to each gene's hypothesis-driven functional group, listed on the right. (B) Samples are plotted by PC1 and PC2 composite gene fold change scores, with geometric encircling to outline B1 vs. B3 group boundaries. (C) Boxplots show PC1 composite gene fold change scores in B1 vs. B3 PFC microvessels. Welch's unpaired t-test was applied to compare B1 and B3 composite scores, with ** indicating p < 0.01. Composite gene fold change scores are significantly larger in B3 vs. B1 microvessels (p = 0.0064, 95% CI: [1.477, 7.956]).
Figure 6
Figure 6
NOS3 antemortem plasma expression is significantly associated with postmortem NOS3 gene expression in PFC capillaries of both B1 and B3 subjects. (A) Univariate regression of NOS3 plasma NPX (from final plasma sample per subject) vs. postmortem microvessel gene log2 fold change demonstrated a significant association between NPX and log2 fold change (β1 =1.022, p = 0.0024, BH-FDR = 0.0511). The shaded region indicates the 95% confidence interval of the regression slope. (B) After adjusting for years until death in multiple regression, there is still a significant association between NOS3 plasma NPX and postmortem capillary gene log2 fold change (β1 = 1.070, p = 0.0031, BH-FDR = 0.0660). For visualization, the adjusted log2 fold change values were calculated as the NPX β1 coefficient plus the partial residual associated between plasma NPX and years until death.
Figure 7
Figure 7
B1 vs. B3 subject plasma expression of protein biomarkers corresponding to genes upregulated in B3 cortical PFC microvessels. (A) NPX values from each subject's last plasma sample for CXCL1, ICAM-2, IL8, PAI-1, SELE, and TIE1. B1 samples are shown in blue and B3 samples are shown in red. Welch's unpaired t-test p-values are shown above the boxes. (B) Plasma NPX values across three longitudinal samples per subject for CXCL1, ICAM-2, IL8, PAI-1, SELE, and TIE1. B1 samples are shown in blue and B3 samples are shown in red. Squares represent the ABC-Braak group mean NPX value at the corresponding plasma sample time point (which is an arbitrary unit, relative to each subject). (C) Relative plasma NPX change from baseline for CXCL1, ICAM-2, IL8, PAI-1, SELE, and TIE1. Values on the y-axis represent net change in plasma NPX from the first plasma sample, which is set to zero for all subjects for visualization. Squares represent the ABC-Braak group mean change in NPX at the corresponding plasma sample time point. Scales are fixed for all six proteins to compare relative temporal stability.
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References

    1. de la Torre JC, Mussivan T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol Res. (1993) 15:146–53. 10.1080/01616412.1993.11740127 - DOI - PubMed
    1. de la Torre JC. The vascular hypothesis of Alzheimer's disease: bench to bedside and beyond. Neurodegener Dis. (2010) 7:116–21. 10.1159/000285520 - DOI - PubMed
    1. Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, et al. . Cerebral blood flow in Alzheimer's disease. Vasc Health Risk Manag. (2012) 8:599–611. 10.2147/VHRM.S34874 - DOI - PMC - PubMed
    1. Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, et al. . Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain. (2012) 135:3749–56. 10.1093/brain/aws271 - DOI - PMC - PubMed
    1. Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. . Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. Brain. (2013) 136:2697–706. 10.1093/brain/awt188 - DOI - PMC - PubMed