Monitoring clusterin and fibrillar structures in aging and dementia

Abstract

Objective: Clusterin is involved in a variety of physiological processes, including proteostasis. Several clusterin polymorphisms were associated with an increased risk of developing Alzheimer's disease, the world-leading cause of dementia. Herein, the effect of a clusterin polymorphism, aging and dementia in the levels of clusterin in human plasma were analysed in a primary care-based cohort, and the association of this chaperone with fibrillar structures discussed.

Methods: 64 individuals with dementia (CDR≥1) and 64 age- and sex-matched Controls from a Portuguese cohort were genotyped for CLU rs1136000 polymorphism, and the plasma levels of clusterin and fibrils were assessed.

Results: An increased prevalence of the CC genotype was observed for the dementia group, although no significant robustness was achieved. CLU rs11136000 SNP did not significantly change plasma clusterin levels in demented individuals. Instead, clusterin levels decreased with aging and even more in individuals with dementia. Importantly, plasma clusterin levels correlated with the presence of fibrillar structures in Control individuals, but not in those with dementia.

Conclusion: This study reveals a significant decrease in plasma clusterin in demented individuals with aging, which related to altered clusterin-fibrils dynamics. Potentially, plasma clusterin and its association with fibrillar structures can be used to monitor dementia progression along aging.

Keywords: Aging; Alzheimer’s disease; Clusterin; Dementia; Fibrils.

Fig. 1

Levels of Clusterin in plasma of Control and CDR≥1 individuals. The levels of clusterin were evaluated in plasma of Control (○) and CDR≥1 individuals (●) as whole groups (a), and according to the CLU rs1113600 SNP genotype (b). A t-test was applied to compare the Control and CDR≥1 groups (p = 0.3515), while a Two-Way ANOVA with multiple comparisons was used to test the effect of the genotypes in the two groups (p=0.7199). All samples were normalized to the reference sample and clusterin levels are represented as fold changes. Bars represent mean ± s.e.m.

Fig. 2

Plasma levels of Clusterin in Control and CDR≥1 individuals, with aging. Levels of plasma clusterin were assessed by immunoblotting and plotted according to the age of each individual. Pearson’s coefficient (Pearson r) was applied to test the correlation of both groups, (a) Controls (○) and (b) CDR≥1 (●), with aging. In Controls, (ns) stands for non-significant and p=0.1543; in CDR≥ 1, p=0.0003 (***). All samples were normalized to the reference sample and clusterin levels are represented as fold changes. Lines represent a linear regression fit with corresponding 95% confidence bands (dashed lines).

Fig. 3

Levels of Fibrillar structures in Control and CDR≥1 individuals. The levels of fibrils were evaluated in plasma of Control (□) and CDR≥1 individuals (■) using a two-tailed Mann-Whitney test (p=0.7190). All samples were normalized to the reference sample and fibrils levels are represented as fold changes. Bars represent mean ± s.e.m.

Fig. 4

Correlation between clusterin and fibrillar structures. The levels of clusterin and fibrils were independently evaluated in plasma of (a) Control (◊) and (b) CDR≥1 individuals (♦), and matched values plotted. Correlations were evaluated by Spearman coefficients (r), with (**) p=0.0010 for Controls and (ns) p=0.3252 for CDR≥1. All samples were normalized to the reference sample and fibrils vs clusterin levels are represented as fold changes. Lines represent a linear regression fit with corresponding 95% confidence bands (dashed lines).