Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain
Por:
Ledreux, A, Thomas, S, Hamlett, ED, Trautman, C, Gilmore, A, Hager, ER, Paredes, DA, Margittai, M, Fortea, J, Granholm, AC
Publicada:
1 sep 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 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.
Filiaciones:
Ledreux, A:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
Thomas, S:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
Hamlett, ED:
Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA
Trautman, C:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
Gilmore, A:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
Hager, ER:
Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA
Paredes, DA:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
Margittai, M:
Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA
Fortea, J:
Hosp Santa Creu & Sant Pau, Barcelona 08041, Spain
Catalan Syndrome Fdn, Barcelona 08041, Spain
Granholm, AC:
Univ Denver, Knoebel Inst Hlth Aging, Denver, CO 80208 USA
gold, Green Published
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