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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]

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