Amyloid
-peptide (A
), the patho

Amyloid
-peptide (A
), the pathogenic agent of Alzheimerdisease, is a physiological metabolite whose levels are constantlycontrolled in normal brain. Recent studies have demonstratedthat a fraction of extracellular A
is associated with exosomes,small membrane vesicles of endosomal origin, although the fateof A
in association with exosome is largely unknown. In thisstudy, we identified novel roles for neuron-derived exosomesacting on extracellular A
, i.e. exosomes drive conformationalchanges in A
to form nontoxic amyloid fibrils and promoteuptake of A
by microglia. The A
internalized together withexosomes was further transported to lysosomes and degraded.We also found that blockade of phosphatidylserine on the surface of exosomes by annexin V not only prevented exosomeuptake but also suppressed A
incorporation into microglia. Inaddition, we demonstrated that secretion of neuron-derivedexosomes was modulated by the activities of sphingolipidmetabolizing enzymes, including neutral sphingomyelinase 2(nSMase2) and sphingomyelin synthase 2 (SMS2). In transwellexperiments, up-regulation of exosome secretion from neuronalcells by treatment with SMS2 siRNA enhanced A
uptake intomicroglial cells and significantly decreased extracellular levelsof A
. Our findings indicate a novel mechanism responsible forclearance of A
through its association with exosomes. Themodulation of the vesicle release and/or elimination may alterthe risk of AD.