Selenoprotein P and its potential role in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease associated with cognitive decline, loss of memory, and progressive cerebral atrophy. The trace element selenium (Se) is known to be involved in brain pathology. Selenoprotein P (SELENOP), as the main Se transport protein, is, to a great extent, responsible for maintaining Se homeostasis and the hierarchy of selenoprotein expression in the body. Adequate Se supply through SELENOP is vital for proper brain development and function. Additionally, SELENOP may be implicated in pathological processes in the central nervous system, including those in AD. The current review summarizes recent findings on the possible role of SELENOP in AD, with a focus on probable mechanisms: Se delivery to neurons, antioxidant activity, cytoskeleton assembly, interaction with redox-active metals (e.g., copper and iron), and misfolded proteins (amyloid beta and tau protein). The use of SELENOP as a biomarker of Se status is also briefly discussed. Epidemiological studies on Se supplementation are beyond the scope of the current review.

Selenium speciation analysis in the cerebrospinal fluid of patients with Parkinson's disease.

BACKGROUND: The aim of the study was to investigate if speciation analysis by liquid chromatography coupled to mass spectrometry could be used to detect organic and inorganic binding forms of selenium in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and age-matched control subjects (AMC). METHODS: PD patients and control subjects were enrolled from three different neurological departments. CSF samples were collected according to standardized biomarker protocols and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for total selenium determination and ion exchange chromatography (IEC) hyphenated to ICP-MS for selenium speciation analysis. RESULTS: 75 PD patients and 68 age-matched controls were enrolled for speciation analysis. 8 different species could be detected, but only selenoprotein P (SELENOP), human serum albumin-bound Se (Se-HSA), selenomethionine (Se-Met) and an unidentified Se-compound (U2) presented with more than 50% values above the limit of quantification, without showing significant differences between both groups (p > 0.05). The Se-HSA / Se-Met ratio yielded a significant difference between PD and AMC (p = 0.045). The inorganic species Se-IV and Se-VI were only detectable in a minor part of PD and AMC samples. A highly significant correlation between total selenium levels and SELENOP (PD p < 0.0001; AMC p < 0.0001) and Se-HSA (PD p < 0.0001; AMC p < 0.0001) could be demonstrated, respectively. CONCLUSIONS: Speciation analysis yielded new insight into selenium homeostasis in PD but cannot be used to establish a diagnostic biomarker. The small number of detectable values for Se-IV and Se-VI suggests an inferior role of these potentially neurotoxic binding forms in PD pathology in contrast to other neurodegenerative disorders.

Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite.

Exposure to selenium, and particularly to its inorganic forms, has been hypothesized as a risk factor for amyotrophic lateral sclerosis (ALS), a fast progressing motor neuron disease with poorly understood etiology. However, no information is known about levels of inorganic and some organic selenium species in the central nervous system of ALS patients, and recent observations suggest that peripheral biomarkers of exposure are unable to predict these levels for several Se species including the inorganic forms. Using a hospital-referred case-control series and advanced selenium speciation methods, we compared the chemical species of selenium in cerebrospinal fluid from 38 ALS patients to those of 38 reference neurological patients matched on age and gender. We found that higher concentrations of inorganic selenium in the form of selenite and of human serum albumin-bound selenium were associated with increased ALS risk (relative risks 3.9 (95% confidence interval 1.2-11.0) and 1.7 (1.0-2.9) for 0.1µg/L increase). Conversely, lower concentrations of selenoprotein P-bound selenium were associated with increased risk (relative risk 0.2 for 1µg/L increase, 95% confidence interval 0.04-0.8). The associations were stronger among cases age 50 years or older, who are postulated to have lower rates of genetic disease origin. These results suggest that excess selenite and human serum albumin bound-selenium and low levels of selenoprotein P-bound selenium in the central nervous system, which may be related, may play a role in ALS etiology.

Selenium speciation in paired serum and cerebrospinal fluid samples.

Se speciation was performed in 24 individual paired serum and cerebrospinal fluid (CSF) samples from neurologically healthy persons. Strong anion exchange (SAX) separation, coupled to inductively coupled plasma-dynamic reaction cell-mass spectrometry (ICP-DRC-MS), was employed. Species identification was done by standard matched retention time, standard addition and by size exclusion chromatography followed from SAX (2-D SEC-SAX-ICP-DRC-MS) and by SAX followed from CE-ICP-DRC-MS (2-D SAX-CE-ICP-DRC-MS). Limit of detection (LoD, 3×standard deviation (SD) of noise) was in the range of 0.026-0.031 µg/L for all investigated species and thus was set uniformly to 0.032 µg/L. Quality control for total Se determination was performed by analysing control materials "human serum" and "urine", where determined values met target values. Several Se species were found in both sample types having following median values (sequence: serum/CSF, each in µg Se/L): total Se, 58.39/0.86; selenoprotein P (SePP), 5.19/0.47; Se-methionine (SeM), 0.23/ 65 µg/L; however, SePP(-CSF) appeared independent of SePP(-serum). For Se-HSA(-serum) versus (vs.) Se-HSA(-CSF), a weak linear relationship was found (r(2)=0.1722). On the contrary, for anti-oxidative Se-enzymes, higher r (2) values were calculated: GPx(-serum) vs. GPx(-CSF), r(2)=0.3837; TrxR(-serum) vs. TrxR(-CSF), r(2)=0.6293. Q(-Se-species) values (= ratios of CSF(-Se-species)/serum(-Se-species)) were compared with the Q (-Alb) value (HSA(-CSF)/HSA(-serum)=clinical index of NB integrity) for deeper information about NB passage of Se species. The Q (-Se-HSA) value (3.8×10(-3)) was in accordance to the molecular mass dependent restriction at NB (Q(-Alb) at 5.25×10(-3)). Increased Q values were seen for TrxR (21.3×10(-3)) and GPx (8.3×10(-3)) which are not (completely) explained by molecular size. For these two anti-oxidative Se-enzymes (GPx, TrxR), we hypothesize that there might be either a facilitated diffusion across NB or they might be additionally synthesized in the brain.