Selective modulation of amyloid-β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels |
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Authors: | Samer O Abdul-Hay Praneeth Edirisinghe Gregory R J Thatcher |
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Institution: | Department of Medicinal Chemistry &Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA |
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Abstract: | Gamma‐secretase modulators (GSMs) include selected non‐steroidal anti‐inflammatory drugs such as flurbiprofen that selectively lowers the neurotoxic amyloid‐β peptide Aβ1–42. GSMs are attractive targets for Alzheimer’s disease, in contrast to ‘inverse GSMs,’ such as fenofibrate, which selectively increase the level of Aβ1–42. A methodology for screening of Aβ modulating drugs was developed utilizing an Aβ‐producing neuroblastoma cell line stably transfected with mutant human amyloid precursor protein, immunoprecipitation of Aβ peptides, and mass spectroscopic quantitation of Aβ1–37/Aβ1–38/Aβ1–40/Aβ1–42 using an Aβ internal standard. The unexpected conclusion of this work was that in this system, drug effects are independent of γ‐secretase. The methodology recapitulated reported results for modulation of Aβ by GSMs. However, control experiments in which exogenous Aβ1–40/Aβ1–42 was added (i) to drug‐treated wild‐type cells or (ii) to conditioned media from these wild‐type cells, gave comparable patterns of Aβ modulation. These results, suggesting that drugs modulate the ability of cell‐derived factors to degrade Aβ, was interrogated by adding protease inhibitors and performing molecular weight cut‐off fractionation. The results confirmed that modulation of Aβ1–40/Aβ1–42 was mediated by selective proteolysis. Treatment of N2a cells with flurbiprofen or fenofibric acid selectively enhanced Aβ1–42 clearance by extracellular proteolysis; treatment with HCT‐1026 or fenofibrate (esters of flurbiprofen and fenobric acid) inhibited clearance of Aβ1–40 and Aβ1–42. |
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Keywords: | Alzheimer's disease amyloid non-steroidal anti-inflammatory drug protease |
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