Bioenergetic impairment in animal and cellular models of Alzheimer's disease: PARP-1 inhibition rescues metabolic dysfunctions

Sara Martire, Andrea Fuso, Luciana Mosca, Elena Forte, Virginia Correani, Mario Fontana, Sigfrido Scarpa, Bruno Maras, Maria D'Erme

Research output: Contribution to journalArticle

Abstract

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.

Original languageEnglish
Pages (from-to)307-324
Number of pages18
JournalJournal of Alzheimer's Disease
Volume54
Issue number1
DOIs
Publication statusPublished - Aug 23 2016

Keywords

  • Alzheimer's disease
  • Bioenergetic metabolism
  • Mitochondria
  • PARP-1
  • PKM2

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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  • Cite this

    Martire, S., Fuso, A., Mosca, L., Forte, E., Correani, V., Fontana, M., Scarpa, S., Maras, B., & D'Erme, M. (2016). Bioenergetic impairment in animal and cellular models of Alzheimer's disease: PARP-1 inhibition rescues metabolic dysfunctions. Journal of Alzheimer's Disease, 54(1), 307-324. https://doi.org/10.3233/JAD-151040