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 ␤-peptide (A␤) from the ␤-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular A␤ by microglia. The statin-dependent clearance of extracellular A␤ is mainly exerted by insulindegrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and A␤ 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␤. Alzheimer disease (AD)3 is associated with extracellular deposits of the amyloid ␤-peptide (A␤) and intraneuronal aggregates of hyperphosphorylated Tau protein in the brain (1). Evidence suggests that the pathogenesis of AD involves deleterious neurotoxic effects of aggregated A␤ peptides (2), which are derived by sequential proteolytic processing of the ␤-amyloid precursor protein (APP) by ␤-and ␥-secretases (3). APP can also be cleaved in a nonamyloidogenic pathway that involves initial cleavage by ␣-secretase within the A␤ domain that precludes the later generation of A␤ peptides (4). Brain A␤ levels are not only determined by the rate of production but also by different clearance mechanisms, including receptor-mediated endocytosis/phagocytosis and subsequent degradation in the endosomal/lysosomal compartment, transcytosis via the blood-brain barrier, as well as proteolytic degradation of extracellular A␤ by cell surface-localized and secreted proteases (5-10).Several studies indicated a dysregulation of lipid metabolism as an important aspect of AD-associated neurodegeneration. In particular, increased cholesterol levels seem to correlate with increased AD risk. Retrospective studies revealed the beneficial effects of statins (11). However, molecular mechanisms by which statins could offer protection against AD remain to be characterized in detail (12, 13). Most studies with cultured cells and animal models indicate that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) could decrease the generation of A␤ by promoting nonamyloidogenic processing of APP. Other studies also showed that extraction of cholesterol from cellular membranes by cyclodextrins differentially affects A␤ generation. Although strong reduction of cholesterol decreased A␤ generation, a moderate extraction rather promoted the secretion of A␤. These effects were attributed to alterations in the distribution of APP and secretases within membrane microdomains (14 -18). In ...

Background: Amyloid-␤ peptide (A␤) is degraded by different proteases. We recently demonstrated phosphorylation of A␤. Results: Phosphorylation of A␤ decreases its clearance by microglial BV-2 cells and selectively inhibits the cleavage by insulindegrading and angiotensin-converting enzymes. Conclusion: Phosphorylation at Ser-8 negatively regulates A␤ degradation. Significance: Phosphorylation could play a dual role in A␤ metabolism. It decreases the clearance by microglial cells and also promotes A␤ aggregation. Accumulation of amyloid-␤ peptides (A␤) in the brain is a common pathological feature of Alzheimer disease (AD).Aggregates of A␤ are neurotoxic and appear to be critically involved in the neurodegeneration during AD pathogenesis. Accumulation of A␤ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the ␥-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD. However, recent data also indicate a decreased clearance rate of A␤ in AD brains. We recently demonstrated that A␤ undergoes phosphorylation by extracellular or cell surface-localized protein kinase A, leading to increased aggregation. Here, we provide evidence that phosphorylation of monomeric A␤ at Ser-8 also decreases its clearance by microglial cells. By using mass spectrometry, we demonstrate that phosphorylation at Ser-8 inhibited the proteolytic degradation of monomeric A␤ by the insulin-degrading enzyme, a major A␤-degrading enzyme released from microglial cells. Phosphorylation also decreased the degradation of A␤ by the angiotensin-converting enzyme. In contrast, A␤ degradation by plasmin was largely unaffected by phosphorylation. Thus, phosphorylation of A␤ could play a dual role in A␤ metabolism. It decreases its proteolytic clearance and also promotes its aggregation. The inhibition of extracellular A␤ phosphorylation, stimulation of protease expression and/or their proteolytic activity could be explored to promote A␤ degradation in AD therapy or prevention.Alzheimer disease (AD) 3 is characterized by the progressive deposition of amyloid-␤ peptides (A␤) in the brain (1, 2). A␤ derives from proteolytic processing of the amyloid precursor protein involving sequential cleavages by enzymes called ␤-and ␥-secretases (3, 4). A critical role of A␤ in the pathogenesis of AD is strongly supported by several mutations within the genes encoding the amyloid precursor protein itself or the two presenilins that represent the proteolytically active components of the ␥-secretase complex. All of these mutations affect the production and/or aggregation of A␤ and cause early-onset forms of familial AD (5-7). Although early-onset familial AD appears to be commonly associated with an elevated production of aggregation-prone A␤ variants, it remains unclear whether increased A␤ generation also contributes to the much more common form of late-onset AD. Recent evidence rather indicated a decreased clearance rate of A␤ in AD compared with control brains (8 -10).Several...