Lawrence Rajendran,
Velux Stiftung Professor for Systems and Cell Biology of Neurodegeneration,
University of Zurich
Prof. Lawrence Rajendran is a renowned expert in the cell biology of Alzheimer’s disease. He studied the mechanisms by which cells regulate the production of the amyloid ß (Aß) peptide, a central molecule in the pathogenesis of Alzheimer’s disease. Particularly, he studied the involvement of lipids and membrane trafficking in Aß metabolism and using biochemical, genetic and cell biological tools, he identified early endosomes to be the organelles responsible for Aß production. He discovered a novel exosomal pathway through which the Aß peptides could exit the cell to accumulate in the form of amyloid plaques. Two years after identifying the subcellular organelle responsible for Aß production, he showed that ß-secretase, the rate-limiting enzyme in Aß production, can be efficiently inhibited if a soluble ß-secretase inhibitor is targeted to the endosomes via membrane anchoring. This work provided key insights into designing effective drugs for membrane-associated targets. Thus his lab focuses on understanding the role of extracellular vesicles in Alzheimer’s disease. Dr. Rajendran has made pioneering contributions in the field of exosomes and neurodegeneration. He is one of the founding members of the International Society for Extracellular Vesicles (ISEV) and served in the board as the Steering committee member. He is the founder of the Facebook platform for the ISEV. He is the founder and Chairman of Sciencematters, the next generation science journal platform. On the social side, He is the founder of raise.rural, a non-profit organization dedicated to support rural students in India to pursue research. He has won many awards and honors including the German Neuroscience Society's Schilling's prize, the Breuer Award, the National Medal of Honor and the President’s Prize by the Govt. of Panama, German Alzheimer’s Hirnliga’s Steinberg-Krupp Prize, Outstanding Young Investigator award of the Alzheimer’s Drug Discovery Foundation, The Boehringer Ingelheim Apopis Prize, European Neuroscience Society Award and a University gold medalist in both Bachelors and Masters. Rajendran featured in the 2009 World's top 100 Scientists.
Exosomes in the Pathogenesis and Diagnosis of Alzheimer’s and Neurodegenerative Diseases
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 presenting opportunity for exosome-based diagnostics.
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