Aß leads to Ca²âº signaling alterations and transcriptional changes in glial cells.

The pathogenesis of Alzheimer's disease includes accumulation of toxic amyloid beta (Aß) peptides. A recently developed cell-permeable peptide, termed Tat-Pro, disrupts the complex between synapse-associated protein 97 (SAP97) and the α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), thereby leading to an alteration of the trafficking of the enzyme, which is important for nonamyloidogenic processing of amyloid precursor protein (APP). We report that Tat-Pro treatment, as well as the treatment with exogenous Aß, deregulates Ca(2+) homeostasis specifically in astrocytes through increased expression of key components of Ca(2+) signaling, metabotropic glutamate receptor-5 and inositol 1,4,5-trisphosphate receptor-1. This is accompanied by potentiation of (S)-3,5-dihydroxyphenylglycine-induced Ca(2+) transients. Calcineurin inhibition reverts all these effects. Furthermore, our data demonstrate that astrocytes express all the components for the amyloidogenic and nonamyloidogenic processing of APP including APP itself, beta-site APP-cleaving enzyme 1 (BACE1), ADAM10, γ-secretase, and SAP97. Indeed, treatment with Tat-Pro for 48 hours significantly increased the amount of Aß(1-42) in the medium of cultured astrocytes. Taken together, our results suggest that astroglia might be active players in Aß production and indicate that the calcium hypothesis of Alzheimer's disease may recognize glial cells as important intermediates.

The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis.

In the present study, we performed a systematic review and meta-analysis on published data to examine the impact of CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms on tacrolimus dose-adjusted trough levels (C0/D) and acute rejection rates in adult renal transplant patients. Despite the presence of significant heterogeneity in all comparisons, random-effects model showed significantly higher tacrolimus C0/D in CYP3A53/3 compared with CYP3A51 allele carriers, either in the overall analysis and when stratifying for ethnicity or time of post-transplantation (≤1, 3-6, 12-24 months). In contrast, no consistent evidence of an effect of the ABCB1 3435C>T variant was detected on tacrolimus C0/D, except for a modest effect limited to the first month after renal transplantation. In addition, from the current evidence available, CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms seem to have little or no effect on the acute rejection rates in renal transplant patients under immunosuppressive therapy with tacrolimus.

Modulatory effect of acetyl-L-carnitine on amyloid precursor protein metabolism in hippocampal neurons.

Alzheimer Disease is the most common chronic neurodegenerative disorder associated with aging. Nevertheless, its pharmacological therapy is still an unresolved issue. In double-blind controlled studies, acetyl-L-carnitine (ALC) demonstrated beneficial effects on Alzheimer's disease. However, the mechanisms behind its neuroprotective ability remain to be fully established. In this study, the effect of acetyl-L-carnitine on amyloid precursor protein (APP) metabolism was investigated by in vitro models, both in a neuroblastoma cell line and in primary hippocampal cultures. We found that ALC treatment stimulates alpha-secretase activity and physiological APP metabolism. In particular, ALC favors the delivery of ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for alpha-secretase) to the post-synaptic compartment, and consequently positively modulates its enzymatic activity towards APP. Our findings suggest that the benefits of ALC reported in previous clinical studies are underscored by the specific biological mechanism of this compound on APP metabolism. In fact, ALC can directly influence the primary event in Alzheimer's disease pathogenesis, i.e. the Amyloid beta cascade, promoting alpha-secretase activity and directly affecting the release of the non amyloidogenic metabolite.