title: Phosphorylation of amyloid-β peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.
abstract: Accumulation of amyloid-β peptides (Aβ) in the brain is a common pathological feature of Alzheimer disease (AD). Aggregates of Aβ are neurotoxic and appear to be critically involved in the neurodegeneration during AD pathogenesis. Accumulation of Aβ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the γ-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD. However, recent data also indicate a decreased clearance rate of Aβ in AD brains. We recently demonstrated that Aβ undergoes phosphorylation by extracellular or cell surface-localized protein kinase A, leading to increased aggregation. Here, we provide evidence that phosphorylation of monomeric Aβ 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 Aβ by the insulin-degrading enzyme, a major Aβ-degrading enzyme released from microglial cells. Phosphorylation also decreased the degradation of Aβ by the angiotensin-converting enzyme. In contrast, Aβ degradation by plasmin was largely unaffected by phosphorylation. Thus, phosphorylation of Aβ could play a dual role in Aβ metabolism. It decreases its proteolytic clearance and also promotes its aggregation. The inhibition of extracellular Aβ phosphorylation, stimulation of protease expression and/or their proteolytic activity could be explored to promote Aβ degradation in AD therapy or prevention.
authors.affiliation: Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.forename: Sandesh
authors.initials: S
authors.lastname: Singh
authors.forename: Désirée
authors.initials: D
authors.lastname: Hinze
authors.forename: Michaele
authors.initials: M
authors.lastname: Josten
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Martin
authors.initials: M
authors.lastname: Siepmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D005341:Fibrinolysin; D007339:Insulysin