Pharmacological targeting of the Î 2-amyloid precursor protein intracellular domain

Caterina Branca, Ilenia Sarnico, Roberta Ruotolo, Annamaria Lanzillotta, Arturo Roberto Viscomi, Marina Benarese, Vanessa Porrini, Luca Lorenzini, Laura Calzà, Bruno Pietro Imbimbo, Simone Ottonello, Marina Pizzi

Research output: Contribution to journalArticle

Abstract

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-(3â €2,4â €2-dichloro-2-fluoro[1,1â €2-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 AÎ 2 42 to the less toxic AÎ 2 38 peptide without affecting APP-C-terminal fragment, nor APP levels. As revealed by photoaffinity labeling, CHF5074 does not interact with Î 3-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.

Original languageEnglish
Article number04618
JournalScientific Reports
Volume4
DOIs
Publication statusPublished - Apr 9 2014

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

Branca, C., Sarnico, I., Ruotolo, R., Lanzillotta, A., Viscomi, A. R., Benarese, M., Porrini, V., Lorenzini, L., Calzà, L., Imbimbo, B. P., Ottonello, S., & Pizzi, M. (2014). Pharmacological targeting of the Î 2-amyloid precursor protein intracellular domain. Scientific Reports, 4, [04618]. https://doi.org/10.1038/srep04618