Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

S creening for ADME/Tox properties of compounds is a key step in the drug development process. Three applications defining such properties, namely Cytochrome P450 Inhibition, Serum Protein Binding and P-glycoprotein Interaction were developed and the performance of each was evaluated on Tecan's LabCD-ADMET System. The LabCD-ADMET System is an automated platform which integrates microfluidics, in the form of the centrifugally driven LabCD device; liquid handling and assay robotics, in the form of a modified GENESIS liquid handling workstation; an incubation, spinner, and detection system, the ULTRA LabCD; and platform/application-specific software. The assay approach and the data for each application are presented. Two applications, Cytochrome P450 inhibition and serum protein binding assays, have also been externally validated at leading pharmaceutical companies within Tecan's Early Access Program (EAP). The LabCD-ADMET System provides a miniaturized, integrated, and automated turnkey solution for various ADME/Tox applications. Assay Approach Automation: The miniaturized assays presented here use the LabCD-ADMET System (Figure 1). This system integrates the centrifugally driven microfluidic LabCD (Figure 2 & 3), an Ultra LabCD/microplate reader, and software on the Genesis robotic platform.

No abstract