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Blood Biomarkers for Alzheimer’s Disease in Down Syndrome
Article

Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain

1
Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA
2
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
3
Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, USA
4
Hospital de la Santa Creu i Sant Pau and Catalan Down Syndrome Foundation, 08041 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Giuseppe Lanza
J. Clin. Med. 2021, 10(17), 3931; https://doi.org/10.3390/jcm10173931
Received: 1 August 2021 / Revised: 24 August 2021 / Accepted: 28 August 2021 / Published: 31 August 2021
(This article belongs to the Special Issue Aging in Down Syndrome: Latest Clinical Advances and Prospects)
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. View Full-Text
Keywords: Down syndrome; aging; biomarkers; neuropathology; Alzheimer’s disease Down syndrome; aging; biomarkers; neuropathology; Alzheimer’s disease
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MDPI and ACS Style

Ledreux, A.; Thomas, S.; Hamlett, E.D.; Trautman, C.; Gilmore, A.; Rickman Hager, E.; Paredes, D.A.; Margittai, M.; Fortea, J.; Granholm, A.-C. Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain. J. Clin. Med. 2021, 10, 3931. https://doi.org/10.3390/jcm10173931

AMA Style

Ledreux A, Thomas S, Hamlett ED, Trautman C, Gilmore A, Rickman Hager E, Paredes DA, Margittai M, Fortea J, Granholm A-C. Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain. Journal of Clinical Medicine. 2021; 10(17):3931. https://doi.org/10.3390/jcm10173931

Chicago/Turabian Style

Ledreux, Aurélie, Sarah Thomas, Eric D. Hamlett, Camille Trautman, Anah Gilmore, Emily Rickman Hager, Daniel A. Paredes, Martin Margittai, Juan Fortea, and Ann-Charlotte Granholm. 2021. "Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain" Journal of Clinical Medicine 10, no. 17: 3931. https://doi.org/10.3390/jcm10173931

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