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- W2012050411 abstract "Excessive accumulation of amyloid-beta peptide (Abeta) in the brain is a critical biochemical event in the development of Alzheimer's disease (AD), and understanding the mechanisms that contribute to Abeta accumulation is therefore an area of intense research focus. Abeta accumulation may be due to increased production from the amyloid precursor protein and/or decreased Abeta degradation. Many reports describe conditions that lead to increased Abeta production, but relatively few describe conditions that prevent Abeta degradation. We have previously shown that increased matrix metalloproteinase (MMP) levels can decrease Abeta in vitro. In this study we have incubated Abeta with MMP2 under various conditions then assayed for levels of Abeta degradation using Western blot and mass spectrometry. Here we show that matrix metalloproteinase 2 (MMP2) efficiently degrades Abeta40 and Abeta42 by cleaving between Abeta residues 34 and 35, while MMP9 exhibits considerably less Abeta degrading activity. We found MMP2 degraded synthetic Abeta as well as Abeta extracted from the brains of mice and secreted by cells grown in culture. Significantly, aging the Abeta42 peptide induced the formation of MMP2-resistant oligomers and high molecular weight aggregates, but this was less evident when using aged Abeta40. Co-incubation of Abeta with zinc, but not copper, also inhibited Abeta degradation by MMP2. An elevated Abeta42:Abeta40 ratio and increased Abeta-Zn interactions are evident in the AD brain and are known to induce Abeta amyloid formation. Our data are consistent with the formation of Abeta amyloid structure potently decreasing the Abeta peptide's susceptibility to degradation by MMP2. Our data support the possibility that while the expression and activity of endogenous MMP may be unaltered in the AD brain, the proteinase's capacity to regulate Abeta levels is decreased by factors that promote Abeta amyloid formation. Therapeutic strategies that target Abeta amyloid may facilitate a decrease in the brain Abeta burden by restoring the normal Abeta-degrading capacity of MMP2." @default.
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- W2012050411 date "2008-07-01" @default.
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- W2012050411 title "P1-483: Abeta degradation by matrix metalloproteinase 2 is prevented by factors that induce Abeta amyloid formation" @default.
- W2012050411 doi "https://doi.org/10.1016/j.jalz.2008.05.1066" @default.
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