Overlap between pathways significantly enriched with differentially expressed genes identified by microarray and RNA-sequencing.

<p>(<b>a</b>) Overlap of pathways enriched with upregulated genes together with the five most significant overlapping pathways. (<b>b</b>) Overlap of pathways enriched with downregulated genes together with the five most significant overlapping pathways.</p

Tracking peripheral biomarkers identified from the causal mapping of PD brain.

<p>(<b>a</b>) High confidence biomarkers consistently identified for PD cortex, striatum, and substantia nigra (S. nigra) using microarray analysis. Upregulated biomarkers are shown on the left together with fold changes in the three brain regions, downregulated biomarkers on the right. (<b>b</b>) Functional biomarker panel that combines DEGs, high confidence biomarkers shown in (a) and genes from the causal map. (<b>c</b>) Assessment of biomarkers in brain (top panels)(substantia nigra, SN) and blood (bottom panels) from age-matched control and PD patients using QuantiGene technology from Panomics. * <i>p</i>≤0.05 and ** <i>p</i>≤0.01 as determined using a two-tailed unpaired t-test with Welch's correction.</p

Identification of pathways dysregulated in PD-brain regions, and the overlap of differentially expressed genes (DEGs) between the PD-affected brain regions.

<p>The 10 key pathways most significantly enriched for DEGs in substantia nigra (<b>a</b>), striatum (<b>b</b>) and cortex (<b>c</b>) of PD brains compared to control as measured by microarray. Enrichments for upregulated genes are shown on the left, for downregulated genes on the right. The numbers of DEGs populating each pathway are denoted in the right columns (#DEGs). (<b>d</b>) Overlap between DEGs in PD cortex and striatum as measured by microarrays. The overlap of upregulated genes is shown on the left, the overlap of downregulated genes on the right. (<b>e</b>) Overlap between DEGs in striatum and substantia nigra (S.nigra) as measured by microarrays. The overlap of upregulated genes is shown on the left, the overlap of downregulated genes on the right. (<b>f</b>) Overlap between DEGs in PD cortex and substantia nigra (S. nigra) as measured by microarrays. The overlap of upregulated genes is shown on the left, the overlap of downregulated genes on the right. (<b>g</b>) Overlap between DEGs in PD cortex, striatum and substantia nigra (S. nigra) as measured by microarrays. The overlap of upregulated genes is shown on the left, the overlap of downregulated genes on the right.</p

Protein alterations in PD brain are dominated by mitochondrial and lipid transport defects, and are largely independent of transcriptional changes.

<p>(<b>a</b>) Overlap between proteins and differentially expressed genes in striatum, as measured by mass spectrometry and microarray technologies. The overlap of upregulated proteins/genes is shown on the left, the overlap of downregulated proteins/genes on the right. (<b>b</b>) Overlap between proteins and differentially expressed genes in PD cortex, as measured by proteomics and microarray technologies. The overlap of upregulated proteins/genes is shown on the left, the overlap of downregulated proteins/genes on the right. (<b>c</b>) Oxidative phosphorylation pathway. The most significantly enriched upregulated pathway for PD cortex based on proteomics data. Red thermometers represent proteins with increased abundance. (<b>d</b>) Regulation of CDK5 in presynaptic signaling. The most significantly enriched downregulated pathway for PD cortex based on proteomics data. Blue thermometers represent proteins with decreased abundance.</p

Overview of brain regions and methodology used in this study.

<p>(<b>a, b</b>) Overview of workflow for functional overview and focused analysis. (<b>a</b>) Expression data for healthy and diseased brain regions are statistically analyzed to obtain differentially expressed genes (DEGs). In the first part, the functional overview, the DEGs are used to identify expression regulators as well as pathways that are significantly enriched with DEGs. (<b>b</b>) In the second part, the focused analysis, pathways that are significantly enriched with expression regulators are combined with pathways that are significantly enriched with DEGs. Combining the two-pathway enrichment results leads to the identification of key pathways, which are the basis for the reconstruction of causal networks. (<b>c</b>) Cartoon representation of different brain regions used in the study, and the associated disease severity of each region denoted by gradations of red. Also shown is connectivity between the substantia nigra, striatum and cortex and the three methods used to interrogate the brain regions (microarray, RNAseq and proteomics).</p

Creation of causal network models for PD brain regions reveals parallel yet distinct dysregulated pathways.

<p>(<b>a</b>) Integrated causal network model for upregulated genes in cortex (1), striatum (2), and substantia nigra (3) based on microarray data. Red thermometers represent upregulated genes. Yellow thermometers correspond to topologically significant genes in cortex (4), striatum (5), and substantia nigra (6). (<b>b)</b> Integrated causal network model for downregulated genes in cortex (1), striatum (2), and substantia nigra (3) based on microarray data. Blue thermometers represent downregulated genes. Yellow thermometers correspond to topologically significant genes in cortex (4), striatum (5), and substantia nigra (6).</p

Discovery of (<i>R</i>)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND006) and (<i>R</i>)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds <b>30</b> (ELND006) and <b>34</b> (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between <b>30</b>, <b>34</b>, Semagacestat <b>41</b>, Begacestat <b>42</b>, and Avagacestat <b>43</b> in mice is made. <b>30</b> lowered Aβ in the CSF of healthy human volunteers