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

Anah Gilmore,Camille Trautman,Daniel A Paredes,Sarah Thomas,Eric D Hamlett,Emily Rickman Hager,Martin Margittai,Ann-Charlotte Granholm,Aurélie Ledreux,Juan Fortea

doi:10.3390/jcm10173931

Abstract

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.

Highlights

Down syndrome (DS) is the most common aneuploidy and cause of intellectual disability of genetic origin, with an incidence of 1 in 600–700 babies [1]
We found that the CD81 and Alix levels were significantly elevated in the neuron-derived small extracellular vesicles (NDEVs) preps compared to the plasma and to the three supernatants collected through the isolation procedure (Figure 3A,B), demonstrating a specific enrichment for extracellular vesicles (EVs) in our preparations
To confirm the enrichment for neuronal EVs in our preparations, we measured the levels of relatively specific neuronal biomarkers (Tau, NF-light and UCH-L1) in the NDEV preps as well as in the matching plasma samples and in the three different supernatants recovered during the isolation process

Summary

Introduction

Down syndrome (DS) is the most common aneuploidy and cause of intellectual disability of genetic origin, with an incidence of 1 in 600–700 babies [1]. The presence of a third copy of a segment of or the entire chromosome 21 (Hsa21) results in the overexpression of several genes, including the amyloid precursor protein (APP) gene. The presence of the amyloid precursor protein (APP) gene on Hsa plays a role in this early onset AD [4,9], but other genes on this chromosome (e.g., RCAN1 and Dyrk1A) might play a role in the development of AD pathology and clinical manifestations of dementia [10,11,12]. Pathological alterations of the microtubule-associated protein Tau occurs early in DS [5,13], leading to the intracellular accumulation of phosphorylated forms of

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