Space and airborne Mined Area Reduction Tools

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SMART: Space and Airborne Mined Area Reduction Tools

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Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank

Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer\u27s disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer\u27s Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer\u27s therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic

CSF Aβ isoform patterns.

<p>Dogs treated with vehicle (N = 15), NB-C8 (N = 3 at 3 hours, N = 3 at 16 hours) and NB-B4 (N = 5 at 6 hours). Mass spectra of the Aβ isoform pattern from dogs treated with placebo (Panel a, upper panel) or NB-C8 16 hours post treatment (Panel a, lower panel). The expanded sections show Aβ1-33, Aβ1-34, Aβ5-38 and Aβ5-40. Aβ1-33 and Aβ5-38 were excluded from quantitative analysis since their peaks partially overlap, making quantification difficult. Absolute (Panels b–c) and normalized (Panels d–e) mass spectral peak intensities of all detected Aβ isoforms. Statistical significances were tested for normalized peak intensities comparing different treatments. For NB-B4, significant differences were seen for Aβ5-40 (P = 0.001), Aβ1-34 (P = 0.001) and Aβ11-40 (P = 0.002). For NB-C8, significant differences were seen between vehicle and treatment at 16 h for Aβ5-40 (P = 0.01) and Aβ1-34 (P = 0.05). Data are means; error bars are SD.</p

Summary of processing pathways.

<p>The main pathways of Aβ peptide release and how these are affected by BACE1 inhibition (arrows indicate absolute and/or relative changes). The APP box shows major APP cleaving secretases with selected cleavage sites that depend on them.</p

Cell medium Aβ isoform patterns.

<p>SH-SY5Y APP695wt cells treated with AZ-20 (Panel a). SHSY-5Y APP695swe cells treated with AZ-20 (Panel b). 7PA2 APP751 V717F cells treated with AZ-20 (Panel c). HeLa-APPswe cells treated with β-secretase inhibitor IV (Panel d). HeLa-APPswe mock and scrambled siRNA-transfected control cells, and cells transfected with single oligo siRNA or pooled siRNA against BACE1 (Panels e). N = 1 for each concentration and treatment.</p

Mass spectra of Aβ isoform patterns in all cell models investigated.

<p>SH-SY5Y APP695wt cells treated with DMSO (Panels a and c), 5 µM β-secretase inhibitor IV (Panel b) or 10 µM AZ-20 (Panel d). SH-SY5Y APP695swe cells treated with DMSO (Panel e) or 10 µM AZ-20 (Panel f). 7PA2 APP751 V717F cells treated with DMSO (Panel g) or 10 µM AZ-20 (Panel h). HeLa APPswe cells treated with DMSO (Panel i) or 10 µM β-secretase inhibitor IV (Panel j). HeLa APPswe scrambled siRNA transfected control cells (Panel k) and cells transfected with single oligo siRNAs against BACE1 (Panel l). The mass-to-charge ratio (m/z) of the [M+H]⁺ ion of Aβ5-38 is very close to that of Aβ1-33, causing the peaks to partially overlap and making quantification difficult, wherefore both isoforms were excluded from quantitative analysis. Those peptides are instead presented in these mass spectra as expanded inserts (except for panels g-h where they are clearly visible).</p

Multivariate analysis and CSF Aβ5-40/Aβ1-34.

<p>Multivariate discriminant analysis of the CSF Aβ pattern for treatment compared with placebo in dogs treated with vehicle (N = 15), NB-C8 (N = 3 at 3 h, N = 3 at 16 h) and NB-B4 (N = 5 at 6 h) (Panels a–b). Score vector results including medians (Panel a). Samples were taken 3 h (open triangles), 6 h (filled squares) or 16 h (filled triangles) after treatment. The groups denoted by “T” were used for constructing the multivariate model while “P” represents the prediction set used for testing the stability of the model. In the construction of the model, all dogs treated with NB-C8 were regarded equal, independent of time after drug administration. Relative contributions of different isoforms to group separations, with increased or decreased relative levels in the treated groups, are shown by white or grey bars, respectively (Panel b). Change of the CSF Aβ5-40/Aβ1-34 ratio in relation to change of CSF Aβ1-40 (Panel c) and CSF Aβ1-42 (Panel d). The Aβ5-40/Aβ1-34 ratio was a more sensitive biomarker than Aβ1-40 and Aβ1-42 in terms of change from baseline (the dotted lines indicate predicted correlations for biomarkers affected equally by treatment). Dogs treated with vehicle (N = 4) and BACE1 inhibitor S obtained from Janssen (N = 4 for each dosage) (Panel e). The CSF Aβ5-40/Aβ1-34 ratio completely separated dogs on active treatment versus placebo (P = 0.005 using the Mann-Whitney U test for comparison of all animals on active treatment versus placebo). Time-dependent dynamics of the ratio in high dose treatment (Panel f).</p