d42d11bd178d784b66ad492646da05c4 270285.pdf 5b122250cf8ca257d7f9e85450fa4db395fd9937 270285.pdf 04baf1b2df473b89afe29f881d6c75b4ec9026c28fef6a89f0872afbf588ba94 270285.pdf Title: Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain Subject: Individuals with Down syndrome (DS) exhibit Alzheimer’s disease (AD) pathology at a young age, including amyloid plaques and neurofibrillary tangles (NFTs). Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions. Keywords: Down syndrome; aging; biomarkers; neuropathology; Alzheimer’s disease Author: Aurélie Ledreux, Sarah Thomas, Eric D. Hamlett, Camille Trautman, Anah Gilmore, Emily Rickman Hager, Daniel A. Paredes, Martin Margittai, Juan Fortea and Ann-Charlotte Granholm Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Sep 8 04:37:08 2021 CEST ModDate: Wed Sep 8 04:59:08 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 23 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 5045749 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MUYRTO+URWPalladioL-Ital Type 1 Custom yes yes no 10 0 OCLPCL+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 FZAPWZ+URWPalladioL-Roma Type 1 Custom yes yes no 19 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 32 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 35 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 57 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Isolation of NDEVs from Human Plasma Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Validation of NDEVs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: In Vitro Seeding and Conformational Tau Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Stereotaxic Surgery Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Immunohistochemistry and Image Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: NDEV Validation and Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Tau Protein Amplification and Aggregate Structure Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Increased p-Tau Staining Intensity 4 Months after the Injection Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Glial Immunostaining Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain Author: Aurélie Ledreux, Sarah Thomas, Eric D. Hamlett, Camille Trautman, Anah Gilmore, Emily Rickman Hager, Daniel A. Paredes, Martin Margittai, Juan Fortea and Ann-Charlotte Granholm Subject: Individuals with Down syndrome (DS) exhibit Alzheimer’s disease (AD) pathology at a young age, including amyloid plaques and neurofibrillary tangles (NFTs). Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions. 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