title: Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions.
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.
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Sara
authors: S
authors: Martire
authors: Department of Psychology, and European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Sapienza University, Roma, Italy.
authors: Andrea
authors: A
authors: Fuso
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Luciana
authors: L
authors: Mosca
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Elena
authors: E
authors: Forte
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Virginia
authors: V
authors: Correani
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Mario
authors: M
authors: Fontana
authors: Department of Surgery "P. Valdoni", Sapienza University, Roma, Italy.
authors: Sigfrido
authors: S
authors: Scarpa
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Bruno
authors: B
authors: Maras
authors: Department of Biochemical Sciences, Sapienza University, Roma, Italy.
authors: Maria
authors: M
authors: d'Erme
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003412:Cricetulus; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D009243:NAD; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Alzheimer’s disease; PARP-1; PKM2; bioenergetic metabolism; mitochondria