Sublethal concentrations of prion peptide PrP106-126 or the amyloid beta peptide of Alzheimer's disease activates expression of proapoptotic markers in primary cortical neurons

Neurodegenerative disorders such as prion diseases and Alzheimer's disease (AD) are characterized by neuronal dysfunction and accumulation of amyloidogenic protein. In vitro studies have demonstrated that these amyloidogenic proteins can induce cellular oxidative stress and therefore may contribute to the neuronal dysfunction observed in these illnesses. Although the neurotoxic pathways are not fully elucidated, recent studies in AD have demonstrated up-regulation of caspases in neurons treated with amyloid beta (Abeta) peptide, suggesting involvement of apoptotic processes. To examine the role of proapoptotic pathways in prion diseases we treated primary mouse cortical neurons with the toxic prion protein peptide PrP106-126 and measured caspase activation and annexin V binding. We found that PrP106-126 induced a rapid and marked elevation in caspase 3, 6, and 8-like activity in neuronal cultures. Increased annexin V binding was observed predominantly on cortical cell neurites in peptide-treated cultures. Interestingly, these effects were induced by sublethal (5-50 microM) or lethal (100-200 microM) concentrations of PrP106-126. Sublethal concentrations of PrP106-126 maintained elevated caspase activation for at least 10 days with no loss of cell viability. Abeta1-40 also up-regulated caspase 3 activity and annexin V binding at both sublethal (5 microM) and lethal (25 microM) concentrations. There were no changes to proapoptotic marker expression in cultures treated with scrambled PrP106-126 (200 microM) or Abeta1-28 (25 microM) peptides. These studies demonstrate that amyloidogenic peptides can induce prolonged activation of proapoptotic marker expression in cultured neurons even at sublethal concentrations. These effects could contribute to chronic neuronal dysfunction and increase susceptibility to additional metabolic insults in neurodegenerative disorders. If so, targeting of therapeutic strategies against neuronal caspase activation early in the disease course could be beneficial in AD and prion diseases.     

In vitro characterization of [(18)F]-florbetaben, an Aβ imaging radiotracer

PurposeAmyloid-β (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD). The noninvasive detection of Aβ plaques may increase the accuracy of clinical diagnosis as well as monitor therapeutic interventions. While [¹¹C]-PiB is the most widely used Aβ positron emission tomography (PET) radiotracer, due to the short half-life of ¹¹C (20 min), its application is limited to centers with an on-site cyclotron and ¹¹C radiochemistry expertise. Therefore, novel [¹⁸F] (half-life 110 min)-labeled Aβ PET tracers have been developed. We have demonstrated that [¹⁸F]-florbetaben-PET can differentiate individuals diagnosed with AD from healthy elderly, Parkinson's disease and frontotemporal lobe dementia (FTLD-tau) patients. While [¹⁸F]-florbetaben-PET retention matched the reported postmortem distribution of Aβ plaques, the nature of [¹⁸F]-florbetaben binding to other pathological lesions comprising misfolded proteins needs further assessment. The objective of this study was to determine whether Florbetaben selectively binds to Aβ plaques in postmortem tissue specimens containing mixed pathological hallmarks (i.e., tau and α-synuclein aggregates).MethodHuman AD, FTLD-tau and dementia with Lewy bodies (DLB) brain sections were analyzed by [¹⁸F]-florbetaben autoradiography and [³H]-florbetaben high-resolution emulsion autoradiography and [¹⁹F]-florbetaben fluorescence microscopy.ResultsBoth autoradiographical analyses demonstrated that Florbetaben exclusively bound Aβ plaques in AD brain sections at low nanomolar concentrations. Furthermore, at concentrations thousand-folds higher than those during a PET scan, [¹⁹F]-florbetaben did not bind to α-synuclein or tau aggregates in DLB and FTLD-tau brain sections, respectively. Detection of [¹⁹F]-florbetaben staining by fluorescence microscopy in several AD brain regions demonstrated that Florbetaben identified Aβ plaques in all brain regions examined.ConclusionThis study provides further evidence that [¹⁸F]-florbetaben-PET is a highly selective radiotracer to assess Aβ plaque deposition in the brain.     

Aortic valve replacement for paraprosthetic leak after transcatheter implantation

Conversion to surgical aortic valve replacement (AVR) has been described as a complication following transcatheter aortic valve implantation. This complication occurs in up to 8% of cases and, to the best of our knowledge, preoperative data and surgical outcomes of such patients have not been properly evaluated. Mild paraprosthetic regurgitation is commonly observed after transcatheter aortic valve implantation and usually leads to a benign clinical course. Unequal distribution of valve calcifications is described as a potential mechanism. We report a case of a perioperative paraprosthetic regurgitation that underwent successful urgent surgical AVR and review the incidence and results of paraprosthetic leaks following transcatheter implantation.