Abstract
The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin-4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 μM. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of γ-secretase components and could, therefore, modify γ-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other "AD accelerator" compounds. In summary, treatment with three Aβ42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adenine / chemistry
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Adenine / pharmacology
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / biosynthesis*
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Amyloid beta-Peptides / genetics
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Animals
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Blotting, Western
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Brain / drug effects*
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Brain / metabolism
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Celecoxib
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Cell Line, Tumor
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Cells, Cultured
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Dose-Response Relationship, Drug
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Electrophoresis, Gel, Two-Dimensional
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Fenofibrate / metabolism
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Fenofibrate / pharmacology
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Mice
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Mice, Inbred C57BL
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Microscopy, Electron, Transmission
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Mitochondria / drug effects
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Mitochondria / ultrastructure
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Mitochondrial Proteins / metabolism
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Muscle Proteins / metabolism
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Neurons / drug effects*
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Neurons / metabolism
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Organic Chemicals / metabolism
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Organic Chemicals / pharmacology*
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Peptide Fragments / biosynthesis*
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Peptide Fragments / genetics
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Prohibitins
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Protein Binding / drug effects
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Purines / metabolism
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Purines / pharmacology
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Pyrazoles / metabolism
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Pyrazoles / pharmacology
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Repressor Proteins / metabolism
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Roscovitine
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Sulfonamides / metabolism
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Sulfonamides / pharmacology
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Voltage-Dependent Anion Channel 1 / metabolism
Substances
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Amyloid beta-Peptides
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IMMT protein, human
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Mitochondrial Proteins
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Muscle Proteins
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Organic Chemicals
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Peptide Fragments
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Prohibitins
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Purines
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Pyrazoles
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Repressor Proteins
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Sulfonamides
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aftin-4
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amyloid beta-protein (1-42)
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Roscovitine
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Voltage-Dependent Anion Channel 1
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Amyloid Precursor Protein Secretases
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Adenine
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Celecoxib
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Fenofibrate