Statins Promote the Degradation of Extracellular Amyloid β-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 beta-peptide (A beta) from the beta-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular A beta by microglia. The statin-dependent clearance of extracellular A beta is mainly exerted by insulindegrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and A beta 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 A beta.