title: Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage.
abstract: Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 billnetzer@gmail.com greengard@rockefeller.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Netzer
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Sinha
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 billnetzer@gmail.com greengard@rockefeller.edu.
authors.forename: Paul
authors.identifier: 0000-0002-4437-0893
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Victor
authors.initials: V
authors.lastname: Bustos
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases
keywords: Alzheimer’s disease; Gleevec; nonamyloidogenic; β-cleavage