Role of PrP(C) Expression in Tau Protein Levels and Phosphorylation in Alzheimer's Disease Evolution.

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic ß-amyloid peptide (Aß) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aß oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrP(C)) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aß are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrP(C) expression in the development of AD, and a putative relationship between PrP(C) and tau processing is emerging. However, the role of tau/PrP(C) interaction in AD is poorly understood. In this study, we show increased susceptibility to Aß-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrP(C) knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrP(C) expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrP(C) in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.

Leishmania infantum: antiproliferative effect of recombinant plant cystatins on promastigotes and intracellular amastigotes estimated by direct counting and real-time PCR.

Two recombinant barley cystatins, HvCPI5 and HvCPI6, have been tested in vitro against promastigotes and intracellular amastigotes of Leishmania infantum in the J774 monocytic cell line. Toxicity of cystatins for J774 cells was also determined. In addition, a comparison between direct counts of intracellular amastigotes and quantitation of burden by Q-PCR was carried out. Low concentrations (2 microM) from both cystatins were unable to inhibit promastigote replication. HvCPI5 was toxic for mammalian cells; 0.1 microM reduced by more than 50% the cell viability. On the contrary, HvCPI6 did not exhibit any toxicity for J774 cells up to 6 microM and inhibited the intracellular amastigote multiplication. Dose-response analysis showed that 4.8 microM HvCPI6 reduced by >90% the intracellular parasite load and had an approximate IC(50) value of 1.5 microM. Comparable results were obtained by direct counting of intracellular amastigotes and Q-PCR. Results point towards the direct inhibition of amastigote multiplication by HvCPI6 and the interest of this recombinant cystatin in the chemotherapy of leishmaniasis.