Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo

Abstract

BackgroundExosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored.ResultsWe here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.ConclusionsThese data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.

Role of amyloid β protein receptors in mediating synaptic plasticity

“…This finding supports the results of their previous research (40). Previously, in studies by An et al and Hu et al (41,42) Rowan used antibodies to block PrPc to reduce the influence of Aβ on electrophysiological changes associated with memory, which supports Strittmatter's conclusions [from the study by Gimbel et al (39)] at a conference on European neuroscience. Bitel et al (43) reported that PrP c and Aβ appeared as aggregates and co-localized in a diabetic rabbit model, which suggested that Aβ and PrP c may interact.…”

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

“…In that study, exosomal PrP c was found to accelerate Aβ fibrilization and suggested to protect against the neurotoxic effects of the oligomeric peptide. A similar mechanism might occur in vivo [62] and we have previously shown that PrP c is highly enriched in exosomes purified from cortical neurons [20]. In this case, one function of the exosomes released into parenchymal interstitial space would be to sequester toxic Aβ oligomers released upon fusion of late endosomes to the cell surface in the vicinity of synapses.…”

The Intestinal Transport of Bovine Milk Exosomes Is Mediated by Endocytosis in Human Colon Carcinoma Caco-2 Cells and Rat Small Intestinal IEC-6 Cells

“…ImageJ (http://imagej.nih.gov/ij/index.html) was used to analyze the exosome size distribution, which averaged 69 6 20 nm in diameter, as expected for exosomes that are smaller than microvesicles, apoptotic bodies, and fat globules (28,31). Exosome purity and identity were confirmed using whole protein extracts from exosomes as described previously (32), using mouse anti-bovine CD63 (AbD Serotec) as a marker for exosomes, rabbit antiserum to bovine a-s1-casein as a marker for the animal species of exosome origin, and goat anti-bovine histone H3 (Santa Cruz Biotechnology) as a negative control (all at 1000-fold dilutions). Bands were visualized using an Odyssey infrared imaging system (Licor, Inc.) and IRDye 800CW-labeled secondary antibodies at a 50,000-fold dilution ( Figure 1B).…”