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Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death.
Brain. 2011 Jun; 134(Pt 6):1658-72.B

Abstract

Alzheimer's disease is characterized by β-amyloid accumulation in the central nervous system. As β-amyloid is neurotoxic in culture, we have explored the mechanisms of toxicity in the search for therapeutic targets for Alzheimer's disease and now identify a key role for poly(ADP-ribose) polymerase in β-amyloid-induced neuronal death. Exposure of hippocampal neuronal/glial co-cultures to β-amyloid peptides activates the glial nicotinamide adenine dinucleotide phosphate oxidase, followed by predominantly neuronal cell death. β-amyloid exposure caused the progressive loss of mitochondrial membrane potential in astrocytes, accompanied by transient mitochondrial depolarizations caused by reversible openings of the mitochondrial permeability transition pore. The transients were absent in cultures from cyclophilin D knockout mice, leaving the slow depolarization available for study in isolation. β-amyloid exposure decreased both nicotinamide adenine dinucleotide fluorescence and oxygen consumption, while provision of mitochondrial substrates reversed the depolarization, suggesting that substrate supply was limiting. Poly(ADP-ribose) polymerase is activated by oxidative stress and consumes nicotinamide adenine dinucleotide, decreasing substrate availability. β-amyloid exposure caused accumulation of the poly(ADP-ribose) polymerase product, poly-ADP-ribose polymers, in astrocytes. Inhibition of either poly(ADP-ribose) polymerase or of the nicotinamide adenine dinucleotide phosphate oxidase prevented the appearance of poly-ADP-ribose polymers and the mitochondrial depolarization. Exposure of co-cultures to β-amyloid for >8 h decreased nicotinamide adenine dinucleotide and mitochondrial membrane potential and increased cell death in neurons, all of which were prevented by poly(ADP-ribose) polymerase inhibitors. Poly-ADP-ribose polymers increased with age in the brains of the TASTPM Alzheimer mouse model. We conclude that β-amyloid-induced neuronal death is mediated by poly(ADP-ribose) polymerase in response to oxidative stress generated by the astrocytic nicotinamide adenine dinucleotide phosphate oxidase.

Authors+Show Affiliations

Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Research, University College London, Queen Square, London WC1N 3BG, UK.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21616968

Citation

Abeti, Rosella, et al. "Beta-amyloid Activates PARP Causing Astrocytic Metabolic Failure and Neuronal Death." Brain : a Journal of Neurology, vol. 134, no. Pt 6, 2011, pp. 1658-72.
Abeti R, Abramov AY, Duchen MR. Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain. 2011;134(Pt 6):1658-72.
Abeti, R., Abramov, A. Y., & Duchen, M. R. (2011). Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain : a Journal of Neurology, 134(Pt 6), 1658-72. https://doi.org/10.1093/brain/awr104
Abeti R, Abramov AY, Duchen MR. Beta-amyloid Activates PARP Causing Astrocytic Metabolic Failure and Neuronal Death. Brain. 2011;134(Pt 6):1658-72. PubMed PMID: 21616968.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. AU - Abeti,Rosella, AU - Abramov,Andrey Y, AU - Duchen,Michael R, PY - 2011/5/28/entrez PY - 2011/5/28/pubmed PY - 2011/7/30/medline SP - 1658 EP - 72 JF - Brain : a journal of neurology JO - Brain VL - 134 IS - Pt 6 N2 - Alzheimer's disease is characterized by β-amyloid accumulation in the central nervous system. As β-amyloid is neurotoxic in culture, we have explored the mechanisms of toxicity in the search for therapeutic targets for Alzheimer's disease and now identify a key role for poly(ADP-ribose) polymerase in β-amyloid-induced neuronal death. Exposure of hippocampal neuronal/glial co-cultures to β-amyloid peptides activates the glial nicotinamide adenine dinucleotide phosphate oxidase, followed by predominantly neuronal cell death. β-amyloid exposure caused the progressive loss of mitochondrial membrane potential in astrocytes, accompanied by transient mitochondrial depolarizations caused by reversible openings of the mitochondrial permeability transition pore. The transients were absent in cultures from cyclophilin D knockout mice, leaving the slow depolarization available for study in isolation. β-amyloid exposure decreased both nicotinamide adenine dinucleotide fluorescence and oxygen consumption, while provision of mitochondrial substrates reversed the depolarization, suggesting that substrate supply was limiting. Poly(ADP-ribose) polymerase is activated by oxidative stress and consumes nicotinamide adenine dinucleotide, decreasing substrate availability. β-amyloid exposure caused accumulation of the poly(ADP-ribose) polymerase product, poly-ADP-ribose polymers, in astrocytes. Inhibition of either poly(ADP-ribose) polymerase or of the nicotinamide adenine dinucleotide phosphate oxidase prevented the appearance of poly-ADP-ribose polymers and the mitochondrial depolarization. Exposure of co-cultures to β-amyloid for >8 h decreased nicotinamide adenine dinucleotide and mitochondrial membrane potential and increased cell death in neurons, all of which were prevented by poly(ADP-ribose) polymerase inhibitors. Poly-ADP-ribose polymers increased with age in the brains of the TASTPM Alzheimer mouse model. We conclude that β-amyloid-induced neuronal death is mediated by poly(ADP-ribose) polymerase in response to oxidative stress generated by the astrocytic nicotinamide adenine dinucleotide phosphate oxidase. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/21616968/Beta_amyloid_activates_PARP_causing_astrocytic_metabolic_failure_and_neuronal_death_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awr104 DB - PRIME DP - Unbound Medicine ER -