title: A Novel Small Molecule Modulator of Amyloid Pathology.
abstract: Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY, USA.|Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovell
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY, USA.|Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.|Universisty of Kentucky Mass Spectrometry Center, Lexington, KY, USA.
authors.forename: Bert C
authors.initials: BC
authors.lastname: Lynn
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Fister
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bradley-Whitman
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.|Department of Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.|Department of Pharmacology, University of Kentucky, Lexington, KY, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use; D009447:Neuroblastoma / Q000473:pathology; D009543:Nifedipine / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; C000626074:BNC-1 benzonaphthyridine; D002121:Calcium Channel Blockers; C497761:NOTCH1 protein, human; D009287:Naphthyridines; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D016704:Synapsins; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); D009543:Nifedipine
keywords: Amyloid-β protein precursor; Elk-1; presenilin-1; presenilin-2