Abstract

Exosomes in the Pathogenesis and Diagnosis of Alzheimer’s and Neurodegenerative Diseases

Lawrence Rajendran, Velux Stiftung Professor for Systems and Cell Biology of Neurodegeneration, University of Zurich

While they play crucial roles in physiological processes, EVs/exosomes also contribute to the development of disease states. Neurodegenerative diseases including Alzheimer’s (AD), Parkinson’s disease (PD) and Prion diseases, are characterized by protein aggregation and deposition in specific brain regions. While the exact pathological significance of these aggregates remains to be conclusively resolved, the biology behind their formation is unclear. Recent findings, on the release and spread of several amyloid-forming proteins, suggest a model where these proteins can be released from affected cells in the form of amyloid seeds, and then re-enter other cells and aid in the spread of the disease. How are these aggregates released from the cells? Once released, how do they form plaques and propagate in the aqueous extracellular space to gain access to their host counterparts? We propose that exosomes, endocytically derived nanovesicles, are a major way to shuttle amyloids out of the cell and aid in the plaque formation. We provide evidence that Aß is generated in early endosomes and is released in association with exosomes. Immunoelectron microscopy on exosomes showed that Aß peptides not only co-fractionated with exosomes but also are physically associated with them. To investigate whether these findings have any bearing on Alzheimer pathology, we performed immunohistochemistry analysis with antibodies against exosomal proteins on brain sections from AD patients, Parkinson patients and age matched control subjects.  Enrichment of Alix, a marker for exosomes, was seen around the small neuritic plaques and a moderate signal in large diffuse plaques in brain sections from all AD patients tested. Alix staining was largely absent in brain sections of control subjects. Similar to Aß, both Tau and a-synuclein are also found in EVs and together this represents a novel mode of amyloid transmissibility and thus presents a great opportunity for exosome-based diagnosis of n