Pharmacological targeting of the β-amyloid precursor protein intracellular domain.
Amyloid precursor protein (APP) intracellular domain (AICD) is a product of APP processing with transcriptional modulation activity, whose overexpression causes various Alzheimer's disease (AD)-related dysfunctions. Here we report that 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid) (CHF5074), a compound that favorably affects neurodegeneration, neuroinflammation and memory deficit in transgenic mouse models of AD, interacts with the AICD and impairs its nuclear activity. In neuroglioma-APPswe cells, CHF5074 shifted APP cleavage from Aβ42 to the less toxic Aβ38 peptide without affecting APP-C-terminal fragment, nor APP levels. As revealed by photoaffinity labeling, CHF5074 does not interact with γ-secretase, but binds to the AICD and lowers its nuclear translocation. In vivo treatment with CHF5074 reduced AICD occupancy as well as histone H3 acetylation levels and transcriptional output of the AICD-target gene KAI1. The data provide new mechanistic insights on this compound, which is under clinical investigation for AD treatment/prevention, as well as on the contribution of the AICD to AD pathology.
1] Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy [2].
Caterina
C
Branca
1] Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy [2].
Ilenia
I
Sarnico
Laboratory of Functional Genomics and Protein Engineering, Biochemistry and Molecular Biology Unit, Department of Life Sciences, University of Parma, Italy.
Roberta
R
Ruotolo
Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy.
Annamaria
A
Lanzillotta
1] Laboratory of Functional Genomics and Protein Engineering, Biochemistry and Molecular Biology Unit, Department of Life Sciences, University of Parma, Italy [2].
Arturo Roberto
AR
Viscomi
Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy.
Marina
M
Benarese
1] Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy [2] IRCCS, San Camillo Hospital, Venice, Italy.
Vanessa
V
Porrini
Department of Veterinary Medicine and Health Science, University of Bologna, Italy.
Luca
L
Lorenzini
Department of Veterinary Medicine and Health Science, University of Bologna, Italy.
Laura
L
Calzà
Research and Development, Chiesi Farmaceutici, Parma, Italy.
Bruno Pietro
BP
Imbimbo
Laboratory of Functional Genomics and Protein Engineering, Biochemistry and Molecular Biology Unit, Department of Life Sciences, University of Parma, Italy.
Simone
S
Ottonello
1] Department of Molecular & Translational Medicine and National Institute of Neuroscience, School of Medicine, University of Brescia, Italy [2] IRCCS, San Camillo Hospital, Venice, Italy.
Marina
M
Pizzi
D000107:Acetylation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000494:pharmacology*; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D051861:Kangai-1 Protein / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C497688:CD82 protein, human; D003521:Cyclopropanes; D006657:Histones; D051861:Kangai-1 Protein; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases