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Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions.
J Alzheimers Dis. 2016 08 10; 54(1):307-24.JA

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+Show Affiliations

Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Psychology, and European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Surgery "P. Valdoni", Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.Department of Biochemical Sciences, Sapienza University, Roma, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27567805

Citation

Martire, Sara, et al. "Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions." Journal of Alzheimer's Disease : JAD, vol. 54, no. 1, 2016, pp. 307-24.
Martire S, Fuso A, Mosca L, et al. Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. J Alzheimers Dis. 2016;54(1):307-24.
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 : JAD, 54(1), 307-24. https://doi.org/10.3233/JAD-151040
Martire S, et al. Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. J Alzheimers Dis. 2016 08 10;54(1):307-24. PubMed PMID: 27567805.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. AU - Martire,Sara, AU - Fuso,Andrea, AU - Mosca,Luciana, AU - Forte,Elena, AU - Correani,Virginia, AU - Fontana,Mario, AU - Scarpa,Sigfrido, AU - Maras,Bruno, AU - d'Erme,Maria, PY - 2016/8/29/entrez PY - 2016/8/29/pubmed PY - 2018/1/30/medline KW - Alzheimer’s disease KW - PARP-1 KW - PKM2 KW - bioenergetic metabolism KW - mitochondria SP - 307 EP - 24 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 54 IS - 1 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/27567805/Bioenergetic_Impairment_in_Animal_and_Cellular_Models_of_Alzheimer's_Disease:_PARP_1_Inhibition_Rescues_Metabolic_Dysfunctions_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-151040 DB - PRIME DP - Unbound Medicine ER -