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Additional file 2: Figure S2. of APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Regional analysis of perivascular hemosiderin deposits identifies the brain cortex in mice of all APOE genotypes and the thalamus in APP/ε2 mice as brain structures susceptible to microbleeds associated with anti-Aβ immunization. Shown are means (± SEM) for counts of all brain perivascular hemosiderin deposits in the brain cortex, the hippocampus, the basal ganglia, the corpus callosum, the thalamus, the septum and the midbrain in APP/ε2 (a), APP/ε3 (b), and APP/ε4 mice (c) (n = 5-11/group). Perivascular hemosiderin deposits were counted on every tenth brain coronal cross-section along the entire rostro-caudal axis of the brain. a through (c) p < 0.0001 (one-way analysis of variance); *p < 0.05, ***p < 0.001, and ****p < 0.0001, TY11-15 control vs. 10D5 mAb treatment for matching brain structures and APOE genotypes (Sidak’s post hoc test). For brain structures where the differences between TY11-15 control and 10D5 mAb treatment groups were not statistically significant p values are not shown. Differences between Age control and TY11-15 groups were non-significant for all structures (Sidak’s post hoc test); p values not shown on the graph. (PDF 419 kb

Additional file 1: Figure S1. of APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Comparative analysis of Aβ plaque load immunostained against N-terminal and central Aβ epitopes revealed no significant differences. a Representative microphotographs of coronal brain sections through the somatosensory cortex from the same TY11-15 control, and 10D5 mAb treated mice of APP/ε4 background, which were immunostained using HJ3.4 mAb directed against the N-terminus of Aβ and 4G8 mAb directed against the mid-portion of Aβ. b Unbiased analysis of the parenchymal Aβ plaque load in the brain cortex revealed by HJ3.4 and 4G8 immunostaining. Values represent mean ± SEM from 10 to 12 animals per group. b p < 0.0001 (one-way analysis of variance); ****p < 0.0001, TY11-15 control vs. 10D5 mAb treatment for matching anti-Aβ immunostains (Sidak’s post hoc test). Differences between HJ3.4 and 4G8 immunostaining in TY11-15 control and 10D5 mAb treatment groups were non-significant; not shown on the graph. Scale bar 50 μm (a). (PDF 423 kb

Additional file 1: Table S1. of A single dose of the Îł-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans

Identified peptides. Peptides identified and quantified in at least four participants in each of the three treatment groups. Quantitative data are presented as percent change relative to CSF sampled at the time point when the drug was administered. The values are normalized to the average relative peptide abundance in the placebo group for each time point. (XLSX 86 kb

Additional file 11: Figure S11. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Cultured primary mouse choroid plexus epithelial cells secrete apoE. A) Representative apoE images from Western blots of the conditional medium from choroidal epithelial cells and astrocytes. B) Primary cultured choroidal epithelial cells (CP) produced similar levels of apoE as astrocytes (astro). Values are mean ± SEM, N = 4. C) Representative image of AQP1, a marker of choroid plexus epithelial cell, expression in the cultured primary mouse choroid plexus. Lack of significant immunolabeling of NeuN (neurons; D) and GFAP (astrocytes; E) in the cultured CP epithelial cells. F) Expression of GFAP in the cultured primary mouse astrocytes. DAPI (blue). (EPS 15343 kb

Additional file 1: Figure S1. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

More GFAP-positive astrocytes on the arterial wall than that on veins. a-e) Representative images of GFAP-positive astrocytes on the wall and around arteries and veins. The vasculature was outline by lectin (green) in NG2dsRed reporter mice and perfusion fixed (PFA) at 15 min. A) Astrocytes (GFAP, blue), B) Vessels (lectin-FITC, green), C) arteries (NG2-dsRed, red), D) endogenous apoE (purple) and E) Merged images. Images of GFAP-positive astrocytes around an artery (identified by the expression of NG2-DsRed and vasculature staining with lectin) as shown in the yellow box in C (F) and a vein (identified by the lack of NG2-DsRed expression but with the vasculature stained with lectin) as shown in the white box in C (G). Scale bars: 100 μm (A-E), 50 μm (F-G). Arrow heads (panel F) identify some astrocytic endogenous apoE. (EPS 7646 kb

Additional file 8: Figure S8. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Lenti-EGFP effectively transduced the choroid plexus. A) Lenti-EGFP unilateral injected into the lateral ventricle preferentially transduced the choroid plexus and ependymal layer but not brain parenchyma at 1 week. DAPI (blue); EGFP (green). B-E) Lenti-EGFP expression in the choroid plexus at 1 week. Images are DAPI (blue; B), AQP1 (red; C); EGFP (green; D) and merged images (E). Scale bar 50 μm. Intraventricular injection of 3 μL lenti-EGFP (1012 TU/ml). N = 5. (EPS 75360 kb

Additional file 10: Figure S10. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Lenti-apoE3 transduced the choroid plexus but not the parenchyma cells. A-H) Representative images showing transduction in the choroidal cells of lenti-apoE3 and lenti-EGFP at 4 weeks after intraventricular delivery. A) Merged image showing choroid plexus (CP; scale bar, 100 μm). B) EGFP (green); C) apoE3 (magenta); D) AQP1 (red); E) merged images of B, C and D (scale bar 50 μm). Arrows show apoE3 in choroidal cells in C and E. F-H) cortex (Cx) showing no transduction (no EGFP) (F, scale bar 200 μm) but the presence of apoE3 (G-H). H, scale bar 50 μm. Lenti-apoE3/lenti-EGFP mixture was delivered intraventicularly (3 μL lenti-human apoE (4.06 × 108 TU/ml) and lenti-EGFP (1012 TU/ml) and after 4 weeks the brains were perfusion fixed followed by immunolabeling. (EPS 41288 kb

Additional file 4: Figure S4. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

ApoE isoforms does not affect cascade blue-dextran radial distribution. Similar radial distribution distances of dextran-cascade blue (CB) in the presence of apoE2 (E2), apoE3 (E3) and apoE4 (E4) at 15 min after their intracisternal injection. Values are mean ± SEM, N = 5-9. (EPS 564 kb

Additional file 2: Figure S2. of Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

ApoE4 radial distribution around arteries is shorter than that of dextran. A) Representative images of radial distribution around arteries but not veins for dextran-cascade blue (inert reference molecule, CB) and apoE4-Alexa647 (apoE-647, purple) after 10 min post-injection in NG2Ds-Red (NG2, red) reporter mice. The vasculature was outlined by intravascular labeling with lectin (green). Scale bar = 100 μm. Arteries (yellow arrow head). Veins (blue arrows). B) A custom made image J plugin was used to generate the mean radial distribution of cascade blue labeled dextran (Dextran-CB, blue) and apoE4-Alexa647 (colored red) from the lectin stained vessel wall (green). Distribution from the vessel wall was determined at 1000 intensity units and maximum intensity indicate saturation at 4096 intensity units (212 – 12 bit image depth). (EPS 32092 kb