Vella, Laura J.;
Su, Huaqi;
Koukoulis, Tiana;
Cheng, Lesley;
Purnianto, Adityas;
Beauchamp, Leah;
McLean, Catriona;
Bush, Ashley I.;
Masters, Colin L.;
Reid, Gavin;
Hill, Andrew F.;
Barnham, Kevin J.
The function and composition of brain tissue derived exosomes in human Alzheimer’s disease : Molecular and cell biology/others
: Molecular and cell biology/others
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Medientyp:
E-Artikel
Titel:
The function and composition of brain tissue derived exosomes in human Alzheimer’s disease : Molecular and cell biology/others
:
Molecular and cell biology/others
Beteiligte:
Vella, Laura J.;
Su, Huaqi;
Koukoulis, Tiana;
Cheng, Lesley;
Purnianto, Adityas;
Beauchamp, Leah;
McLean, Catriona;
Bush, Ashley I.;
Masters, Colin L.;
Reid, Gavin;
Hill, Andrew F.;
Barnham, Kevin J.
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Exosomes are extracellular vesicles (EVs) found in all bodily fluids. They carry the unique biological fingerprint of the parental cell they were released from, making them an ideal source of tissue and disease specific biomarkers and they are key players in cell‐to‐cell communication. Identification of brain derived exosomes (BDEs) in the periphery, for the purpose of AD diagnosis, requires knowledge of the composition of exosomes in the CNS. Moreover, an appreciation of the technical complexities associated with the isolation and characterisation of exosomes. We have taken a rigorous approach to the study of exosomes in AD frontal cortex. We have determined their Aβ and tau content, in addition to uncovering their omic profile.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>EVs were isolated from human frontal cortex as previously described by us (Vella et al JEV 2017), according to ISEV guidelines. Vesicles from neurological control or AD subjects were systematically assessed for morphology, density, size distribution, proteomic, lipidomic, genomic and metal content. The potential of BDE tau to cause conversion was assessed in tau biosensor cells.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>Exosomes are hypothesised to be a source of extracellular Aβ and p‐tau in AD and responsible for the ‘spread’ of these proteins. Here, we identified a pool of extracellular p‐tau and Aβ in AD brain, not associated with exosomes. In aggregation assays however, exosomes from AD subjects caused aggregation in tau biosensor cells, despite the absence of detectable p‐tau. Findings from some of our omic approaches revealed that BDEs recapitulate the lipidomic changes in the tissue, with remodelling in PE lipids in AD BDEs relative to control. While genomic profiling identified 26 highly enriched miRNA.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We determined the composition of brain exosomes in AD with the goal of identifying disease relevant biomarkers and identification of BDEs in the periphery. Lipid and RNA changes in AD frontal cortex were not only recapitulated in BDEs from this region but the dynamic range between disease and control tissues was extended, highlighting the advantage of this approach. Our functional studies suggest that BDEs can corrupt tau in the brain, potentially moving through the CNS in the absence of connected neuronal networks or detectable aggregated tau.</jats:p></jats:sec>