Alzheimer's disease β-amyloid peptides are released in association with exosomes

TLDR

Alzheimer’s disease is characterized by accumulation of β‑amyloid peptides formed by amyloidogenic cleavage of APP, but the intracellular compartment where secretases act and how the resulting β‑amyloid is released extracellularly remain unclear. We demonstrate that β‑cleavage occurs in early endosomes, with β‑amyloid routed to multivesicular bodies and a small fraction secreted via exosomes, and that exosomal proteins accumulate in AD plaques, implicating exosomes in disease pathogenesis.

Abstract

Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of beta-amyloid (Abeta) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The Abeta peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. The endocytic system has been implicated in the cleavages leading to the formation of Abeta. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated Abeta is released into the extracellular milieu are not clear. Here, we show that beta-cleavage occurs in early endosomes followed by routing of Abeta to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of Abeta peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD.