Candidate alzheimer’s disease biomarker mir-483-5p lowers tau phosphorylation by direct erk1/2 repression

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.This work has been supported by the Polish National Science Centre grant OPUS 2018/29 /B/NZ7/02757, by the EU Horizon 2020 FETOPEN grant, agreement no 737390 (ArrestAD), and by the funding from the Polish Ministry of Science and Higher Education within 2016-2020 funds for the implementation of international projects (agreement no 3548/H2020/COFUND/2016/2). A.F. research internship in Portugal was supported by Erasmus fellowship

Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants

Familial (FAD) and sporadic (SAD) Alzheimer's disease do not share all pathomechanisms, but knowledge on their molecular differences is limited. We previously reported that cell cycle control distinguishes lymphocytes from SAD and FAD patients. Significant differences were found in p21 levels of SAD compared to FAD lymphocytes. Since p21 can also regulate apoptosis, the aim of this study was to compare the response of FAD and SAD lymphocytes to oxidative stress like 2-deoxy-D-ribose (2dRib) treatment and to investigate the role of p21 levels in this response. We report that FAD cells bearing seven different PS1 mutations are more resistant to 2dRib-induced cell death than control or SAD cells: FAD cells showed a lower apoptosis rate and a lower depolarization of the mitochondrial membrane. Despite that basal p21 cellular content was lower in FAD than in SAD cells, in response to 2dRib, p21 mRNA and protein levels significantly increased in FAD cells. Moreover, we found a higher cytosolic accumulation of p21 in FAD cells. The transcriptional activation of p21 was shown to be dependent on p53, as it can be blocked by PFT-α, and correlated with the increased phosphorylation of p53 at Serine 15. Our results suggest that in FAD lymphocytes, the p53-mediated increase in p21 transcription, together with a shift in the nucleocytoplasmic localization of p21, confers a survival advantage against 2dRib-induced apoptosis. This compensatory mechanism is absent in SAD cells. Thus, therapeutic and diagnostic designs should take into account possible differential apoptotic responses in SAD versus FAD cells

Molecular characterization of the Corynebacterium pseudotuberculosis hsp60-hsp10 operon, and evaluation of the immune response and protective efficacy induced by hsp60 DNA vaccination in mice

<p>Abstract</p> <p>Background</p> <p>Heat shock proteins (HSPs) are important candidates for the development of vaccines because they are usually able to promote both humoral and cellular immune responses in mammals. We identified and characterized the <it>hsp60-hsp10 </it>bicistronic operon of the animal pathogen <it>Corynebacterium pseudotuberculosis</it>, a Gram-positive bacterium of the class <it>Actinobacteria</it>, which causes caseous lymphadenitis (CLA) in small ruminants.</p> <p>Findings</p> <p>To construct the DNA vaccine, the <it>hsp60 </it>gene of <it>C. pseudotuberculosis </it>was cloned in a mammalian expression vector. BALB/c mice were immunized by intramuscular injection with the recombinant plasmid (pVAX1/<it>hsp60</it>).</p> <p>Conclusion</p> <p>This vaccination induced significant anti-hsp60 IgG, IgG1 and IgG2a isotype production. However, immunization with this DNA vaccine did not confer protective immunity.</p

34. A multicenter randomized study of two regimens in paliative radiotherapy of bone metastases

In this study we compared two methods of radiotherapy in patients with painful bone metastases: 20 Gy in five fraction in five consecutive days vs 8 Gy in one fraction. A total of 115 patients (34 males, 81 females), median age 56 years (23–80), were randomly allocated to one of the treatment arms. In 56 pts. Primary tumor was located in the breast, in 14 pts in the lung, in ten pts in the kidney, in seven pts in the prostate, and in 28 pts in other sites. A total of 146 metastatic bone lesions were irradiated, seventy five (51%) were treated with 20 Gy and seventy one (49%) – with 8 Gy. The most frequent location of metastatic lesions was spine (36%), followed by pelvis (25%), long bones (18%), ribs (12%) and other sites (12%). Treatment techniques included single field (73%) or two parallel opposed fields (27%). Complete pain relief was achieved in 36% of the lesions irradiated with 20 Gy and in 41% of those irradiated with 8 Gy. Partial improvement was observed in 46% and 43% of lesions, respectively. The median time to reappearance of pain in both groups was 5.4 a 4.8 months and 5.0 a 5.4 months respectively. We conclude that a single exposure to 8 Gy is of the same efficacy as 20 Gy in five fractions in pain control of bone metastases and should be recommended as routine management