Exosomes: Vehicles for the Transfer of Toxic Proteins Associated with Neurodegenerative Diseases?

Abstract

Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell–cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer’s disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson’s disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

“…Although our transiently transfected model indicates that large aggregates of misfolded SOD1 from dead or dying cells can be efficiently taken up by neighboring cells, we and others have found that exosomal-mediated transport is relevant for misfolded protein transmission in living cells (17,20), for which we used stably transfected NSC-34 cells that show little cell death (Fig. 1A).…”

Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks

“…Exosomes appear to be vehicles for transfer of toxic proteins such as amyloid-beta-derived peptides and alpha-synuclein in the brain increasing the spread of neurodegeneration in Alzheimer's disease and Parkinson's disease, respectively [95,96]. Furthermore, there is the transfer of the chemokine receptor CCR5 between cells by extracellular vesicles which is a mechanism for the spread of cellular human immunodeficiency virus 1 infection (HIV1) [97].…”

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

“…Abeta results from proteolytic cleavage of amyloid precursor 620 protein (APP). In the amyloidogenic pathway, APP in lipid rafts is cleaved first by 621 Beta--secretase and then by gamma--secretase to generate Abeta (32,33). ABeta 622 protein, and Beta and gamma--secretases are found in lipid rafts, along with 623 GM1 (33).…”

“…Amorphous non--congo red positive 627 plaques develop first, and later mature to B--sheet plaques (35). A--Beta fibrils 628 aggregate into cross--beta--pleated--sheets (36) Abeta has been found in exosomes 629 (32). 630 631…”