Are exosomes driving Alzheimer’s disease pathogenesis?

Neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion disease have distinct clinical manifestations and molecular pathology; however they share common features such as aggregation of disease specific proteins. 

These include tau and β-amyloid (Aβ) in Alzheimer’s disease (AD), α-synuclein (α-syn) in Parkinson’s disease and the prion protein (PrP) in prion disease. Further commonalities exist, namely those observed at the anatomical level revealing spread of these proteins is in a non-random, topographically predictable manner in the brain. Cell-to-cell contact and passive spread were initially deemed responsible; however, more recently small extracellular vesicles, called exosomes, have been proposed to play a role.

Exosomes are released into the extracellular environment by most cell types and play an important role in inter-cellular communication. Once released from the donor cell, exosomes act as discrete vesicles travelling to distant and proximal recipient cells to alter cell function and phenotype. In the case of prion disease, we have shown that exosomes alter recipient cell function by transmitting infectious prions and initiating a cascade of events that further spreads and propagates the disease. The idea that exosomes may also be involved in the spreading of pathology from cell to cell in AD has recently gained considerable attention with tau and Aβ postulated to be trafficked via exosomes by many leaders in the AD field.

This project will take advantage of a new protocol we have developed to isolate and study exosomes in the human AD brain. Techniques employed will include exosome isolation from human and mouse tissue, western blotting, density gradients, dynamic light scattering and electron microscopy. The student will examine the content of brain derived exosomes in AD with the aim of determining the contribution of exosomes to the neurotoxicity and neuropathology that defines disease.

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