Exosomes in Alzheimer’s disease

Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found everywhere in the body. The role of exosomes in cellular functions has in the past years developed from being considered little more than cellular trashcans, to being proven important intercellular messengers and notable contributors to both health and in disease. A vast number of studies have revealed the multiple, and somewhat controversial role of exosomes in Alzheimer’s disease, the most common neurodegenerative disease. Exosomes have been shown to spread toxic amyloid-beta and hyperphosphorylated tau between cells, and they have been suspected of inducing apoptosis and thereby contributing to neuronal loss. On the other hand, exosomes seem to possess the ability to reduce brain amyloid-beta through microglial uptake, and they are known to transfer neuroprotective substances between cells. These features, among many others, make exosomes extremely interesting from the point of view of developing novel therapeutic approaches. The fact that exosomes derived from the central nervous system can be found in bodily fluids also makes them an appealing target for biomarker development, which is not limited only to Alzheimer’s disease.

Formation of exosomes

Plasma membrane budding inwards is triggered by ceramide (CER), forming small vesicles, which then fuse together to form the early endosome. Early endosomes mature into late endosomes, and its limiting membrane continues to invaginate, leading to the formation of the multivesicular body (MVB). MVBs can either fuse with lysosomes (not shown) or with the plasma membrane, releasing its contents as exosomes. ESCRT-complex (endosomal sorting complex required for transport) uses ubiquitin tag for sorting the proteins to be transported. Lipid raft domains formed by SM (sphingomyelin), glycosphingolipids and cholesterol sort proteins independently from ESCRTs. Tetraspanins and annexin are proteins which can be found from all exosomes regardless of their parent cell, and plasma membrane proteins can be specific to the cells from which exosomes are released.

• Exosome contents are transferred between cells to modify target cell function.
• Exosome contents are altered in Alzheimer’s disease.
• Beneficial and harmful effects are associated with exosomes in Alzheimer’s disease.
• Exosomes have potential as diagnostic tools in Alzheimer’s disease.