Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: a potential early sign of AD

Abstract

Background Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer’s disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (Aβ42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated. Trial registration ClinicalTrials.govNCT01041989. Registered on 4 January 2010—retrospectively registered

TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model

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Alzheimer’s disease biomarker profiling in a memory clinic cohort without common comorbidities

“…P-tau/Aβ42 ratio was preferentially selected as a specific marker for Alzheimer’s disease instead of individual markers, as it has been shown that the ratio is superior in assessing amyloid pathology. 28 SNAP-25 was the only synaptic marker that differed between the clinical groups in our material and it has been shown to possess the best discriminatory power to distinguish Alzheimer’s disease from non-Alzheimer patients compared to other synaptic biomarkers, 25 therefore we selected it as a synaptic dysfunction outcome measure. The results of the analysis are summarized in Table 2 .…”

“…24 TRX-80 was quantified by an in-house sandwich ELISA, as previously published. 10,25 All samples were tested in duplicate, and the average was considered for the statistical analyses. To assess for inter-assay variability, three same CSF samples were assayed in every plate, for each biomarker analysis.…”

SIRT2 inhibition rescues neurodegenerative pathology but increases systemic inflammation in a transgenic mouse model of Alzheimer’s disease

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