Small neuron-derived extracellular vesicles from individuals with down syndrome propagate tau pathology in the wildtype mouse brain
Ledreux, A. (Knoebel Institute for Healthy Aging. University of Denver)
Thomas, S. (Knoebel Institute for Healthy Aging. University of Denver)
Hamlett, E.D. (Department of Pathology and Laboratory Medicine. Medical University of South Carolina)
Trautman, C. (Knoebel Institute for Healthy Aging. University of Denver)
Gilmore, A. (Knoebel Institute for Healthy Aging. University of Denver)
Hager, E.R. (Department of Chemistry and Biochemistry. University of Denver)
Paredes, D.A. (Knoebel Institute for Healthy Aging. University of Denver)
Margittai, M. (Department of Chemistry and Biochemistry. University of Denver)
Fortea, Juan (Institut d'Investigació Biomèdica Sant Pau)
Granholm, A.C. (Knoebel Institute for Healthy Aging. University of Denver)

Fecha:	2021
Resumen:	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 hippocam-pus 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.
Nota:	Altres ajuts: National Institutes of Health (R01AG070153/R21AG056974, RF1AG061566); Bright Focus foundation (CA2018010).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Down syndrome ; Aging ; Biomarkers ; Neuropathology ; Alzheimer's disease
Publicado en:	Journal of clinical medicine, Vol. 10 Núm. 17 (january 2021) , p. 3931, ISSN 2077-0383

DOI: 10.3390/jcm10173931
PMID: 34501378

23 p, 4.8 MB

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