No abstract

ObjectivesTo determine the relevance of Mini‐Mental State Examination (MMSE), serum 25‐hydroxyvitamin D (25(OH)D3), and 1,25(OH)2D3 concentrations to mild cognitive impairment (MCI) and various stages of Alzheimer's disease (AD).Materials and MethodsThe study included 230 participants (>74 years) allocated to three main groups: 1‐healthy subjects (HS, n = 61), 2‐patients with MCI (n = 61), and 3‐ patients with Alzheimer's disease (AD) subdivided into three stages: mild (n = 41), moderate (n = 35), and severe AD (n = 32). The cognitive status was evaluated using MMSE. Serum 25 (OH)D3 (ng/ml) and 1,25(OH)2D3 concentrations (pg/ml) were determined by competitive radioimmunoassay.Results MMSE scores and 25(OH)D3 were decreased in MCI and all stages of the AD in both genders. MMSE variability was due to gender in HS (11%) and to 25(OH)D3 in MCI (15%) and AD (26%). ROC analysis revealed an outstanding property of MMSE in diagnosis of MCI (AUC, 0.906; CI 95%, 0.847–0.965; sensitivity 82%; specificity, 98%) and AD (AUC, 0.997; CI 95%, 0.992–1; sensitivity, 100%; specificity, 98%). 25(OH)D3 exhibited good property in MCI (AUC, 0.765; CI 95%, 0.681–0.849; sensitivity, 90%; specificity, 54%) and an excellent property in diagnosis of AD (AUC, 0.843; CI 95%, 0.782–0.904; sensitivity, 97%; specificity, 79%). Logistic analyses revealed that, in MCI, MMSE could predict (or classify correctly) with 97.6% accuracy (Wald, 15.22, β, −0.162; SE, 0.554; OR = 0.115:0.039–0.341; p = .0001), whereas 25(OH)D3 with 80% accuracy (Wald, 41,013; β, −0.213; SE, 0.033; OR = 0.808: 0.757–863; p = .0001). 25(OH)D3 was the only significant predictor for the severe AD and contributed to MMSE variability. Age and gender were significant predictors only in the moderate AD. In patients with MCI, 25(OH)D3 and 1,25(OH)2D3 were correlated men, but in case of the AD, they were correlated in women.Conclusions MMSE and serum 25(OH)D3 concentrations could be useful biomarkers for prediction and diagnosis of MCI and various stages of the AD. The results support the utility of vitamin D supplementation in AD therapy regimen.

Altered vascular reactivity due to endothelial dysfunction, consequent to vascular damage, is observed in rheumatoid arthritis. We investigated the effect of angiotensin (Ang)-(1-7) on vasculature changes in arthritis induced by complete Freund's adjuvant in male Wistar rats. Arthritis decreased soluble receptor for advanced glycation end products (sRAGE) whereas elevated aortic RAGE expression, increased interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), systolic blood pressure and the contractility induced by phenylephrine and KCl. Moreover, arthritis decreased the relaxing effect of acetylcholine. Neither arthritis nor Ang-(1-7) altered sodium nitroprusside relaxation. Ang-(1-7) reversed the effect of arthritis on TNF-α, sRAGE and RAGE expression without any effect on the IL-1β. Ang-(1-7) decreased phenylephrine and KCl contractility, especially in the endothelial-denuded aorta, whereas increased acetylcholine relaxation in the endothelial-intact aorta. Ang-(1-7) could find its place in the treatment protocol of arthritis and vascular diseases.

Reversal of temperature-induced conformational changes in the amyloid-beta peptide, Ab40, by the b-sheet breaker peptides 16-23 and 17-24b ph_384 Background and purpose: Aggregates of the protein amyloid-beta (Ab) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Ab, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. Experimental approach: We investigated ex vivo the temperature-sensitive regions of Ab1-40 (Ab40) and their interactions with octapeptides derived from sequences within Ab40 -b-sheet breaker peptides (bSBP) -using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5-10, 9-14 and 17-21 within Ab40. Key results: Temperature-dependent conformational changes were observed in Ab40 at epitopes 9-14 and 17-21 at 36-38 and 36-40°C respectively. The bSBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, bSBPs 16-23 and 17-24 increased digestion of Ab40 by protease K, indicating a decreased aggregation of Ab40, whereas bSBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that b-sheet formation in Ab40 at 38°C was reduced with bSBPs 16-23 and 17-24. Conclusions and implications:The epitopes 9-14 and 17-21 are the temperature-sensitive regions within Ab40. The bSBPs, Ab16-23 and 17-24 reversed temperature-induced b-sheet formation, and decreased Ab40 aggregation. The results suggest that the 17-23 epitope of Ab40 is crucially involved in preventing Ab40 aggregation and consequent deposition of Ab40 in AD brain.

Amyloidβ-protein (Aβ) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. β-sheet breaker peptides (βSBP) decrease Aβ fibrillogenesis and neurotoxicity by preventing or dissolving misfolded Aβ aggregates. The present study investigated the effects of βSBPs on Aβ40-related neuropathology, memory impairment in 8-armed radial maze and expression of Aβ40 in brain and serum. Aβ40 was injected into amygdaloid nucleus followed 8 days later by octapeptideβSBPs 15-22, 16-23 and 17-24. Aβ40 was detected not only in amygdala, but also in serum. Aβ40 induced cellular changes in amygdala and additionally in hippocampus. Aβ40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The βSBPs decreased Aβ40-induced pathological changes, memory impairment and Aβ40 expression in serum. The βSBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide βSBPs corrected Aβ40-induced memory impairment, and support investigation of βSBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.