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Phosphorylation of amyloid-? peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.

ABSTRACT: 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.

SUBMITTER: Kumar S

PROVIDER: S-EPMC3318721 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Phosphorylation of amyloid-β peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.

Kumar Sathish S Singh Sandesh S Hinze Désirée D Josten Michaele M Sahl Hans-Georg HG Siepmann Martin M Walter Jochen J

The Journal of biological chemistry 20120120 11

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 ...[more]

PMID: 22267728

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Project description:Evolution of glomerulonephritis (GN) to tubulointerstitial disease is a universal antecedent to the development of chronic kidney disease (CKD). There is also evidence that angiotensin converting enzyme (ACE) inhibition may attenuate the development of CKD in some forms of glomerulonephritis. We tested the role of ACE inhibition in a model of GN in which complement-dependent tubulointerstitial disease develops. GN was induced in C57BL/6 mice with intraperitoneal injections of horse spleen apoferritin (HSA) using lipopolysaccharide (LPS) as an adjuvant. Four groups of six animals were studied: saline-injected control mice treated with captopril or water, and GN mice treated with captopril or water. GN developed in all HSA-treated animals. In those receiving captopril, however, proteinuria (albumin/creatinine ratio) was significantly reduced by captopril treatment. Array screening was used to examined the expression of collagen-related genes and determine if these effects could be mediated by regulation of collagen genes. Six genes were identified for further analysis by quantitative RT-PCR. This model demonstrates that tubulointerstitial disease can be attenuated by ACE inhibition, with clinical, histologic, and gene expression measures. All protocols were approved by the Institutional Animal Care and Use Committee at SUNY Upstate Medical University. We employed four groups of six mice each: saline-injected control mice with and without captopril, and GN with and without captopril. C57BL/6 mice were purchased from The Jackson Laboratories (Bar Harbor, ME). Glomerulonephritis (GN) was induced by intraperitoneal (i.p.) injection of 10 mg of apoferritin from horse spleen (HSA, Sigma, St. Louis, MO) five days per week, with i.p. injection of 100 micrograms lipopolysaccharide (LPS, from Salmonella minnesota; EMD Biosciences, La Jolla, CA), as adjuvant, three times per week. Control animals received equal volumes of 0.15 M NaCl by i.p. injection. Injections were begun when the mice were approximately eight weeks of age and were continued for six weeks. Captopril, at 100 mg/kg/day was given in the drinking water. After 9 weeks, the animals were euthanized and kidneys were removed for RNA purification and analysis.

Dataset Information

Phosphorylation of amyloid-? peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.

Publications

Phosphorylation of amyloid-β peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.

Similar Datasets

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