Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion.
Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin-degrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.
Tamboli
Irfan Y
IY
Departments of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
Barth
Esther
E
Christian
Leonie
L
Siepmann
Martin
M
Kumar
Sathish
S
Singh
Sandesh
S
Tolksdorf
Karen
K
Heneka
Michael T
MT
Lütjohann
Dieter
D
Wunderlich
Patrick
P
Walter
Jochen
J
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D055354:Exosomes / Q000378:metabolism*; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D021381:Protein Transport; D015854:Up-Regulation
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D007339:Insulysin; C013165:statine