Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer’s Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL)

Abstract

Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

A selenium species in cerebrospinal fluid predicts conversion to Alzheimer’s dementia in persons with mild cognitive impairment

“…Another limitation is the prospect of unmeasured confounding [ 96 ], which appears to be of particular relevance in epidemiologic studies dealing with Se [ 97 ]. Finally, the association between selenium as Se(VI) and AD risk found in our study may apply only to a population having the Se exposure typical of residents in the study area, already shown in previous studies to be comparable with the Italian national average [ 98 – 100 ], while such association may not necessarily exist in other populations characterized by considerably lower intake of this element [ 90 , 101 ].…”

“…In fact, peripheral biomarkers of exposure, either based on overall Se or on single Se species, may not adequately predict CNS levels, especially in view of the known peculiarities of metabolism and retention of this element in the brain [ 85 , 86 ] and the lack of correlation between some circulating Se species, especially its inorganic forms, with CSF levels [ 15 , 43 , 87 ]. Most case–control studies of AD have focused on peripheral indicators of exposure, such as blood, urine, hair, and nail samples, finding conflicting results ranging from adverse to protective [ 27 , 28 ], while little association was noted with Se CSF levels [ 88 – 90 ].…”

Selenium, selenoprotein P, and Alzheimer's disease: is there a link?

“…A crosssectional study (2003)(2004)(2005) of 2000 adults (≥ 65 y) from four rural sites in two provinces of China, reported a strong association between nail Se concentration (Table 1) and performance in cognitive tests [132]. This is in agreement with the findings of a set of small studies by Cardoso et al [133][134][135], who reported (i) lower levels of plasma and erythrocyte Se concentrations in patients with AD and MCI, (ii) decreased levels of Se in plasma and erythrocytes of AD patients vs. matched controls from São Paulo, Brazil and, (iii) a decreased concentration (p < 0.05) of Se in erythrocytes of AD patients than in healthy controls (28 cases vs. 29 controls) [135], though no difference was observed for total Se in serum or CSF. It needs to be mentioned that in the context of cognitive function in older adults, low plasma Se may result from reduced production of secreted GPX3 and particularly of SELENOP caused by inflammatory cytokines during the acute-phase response [136].…”

“…This should be considered when evaluating the results of EVA [131] and similar studies [132]. As for the small studies of Cardoso et al [133][134][135], these may lack statistical power to be conclusive.…”

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer's Disease

“…Using this approach, we cannot discriminate between selenium incorporated as selenocysteine and that being transported via transient binding to free thiol groups on serum albumin [26]. Chemically inert buffers at physiological pH used for SEC-ICP-MS preserve the integrity of selenium thiol ligands, with the compromise being relatively low separation efficiency [27]. As such, we suspect that Peak #1 contains highly abundant serum albumin followed closely (without resolution) by selenoprotein P. Differentiating the proportional increase in selenium directly attributable to both proteins would require higher resolution chromatographic methods [28], though the effects of the denaturing conditions typically employed on albumin-selenium binding have not been characterized.…”