RGD Reference Report - Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. - Rat Genome Database

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Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death.

Authors: Abeti, R  Abramov, AY  Duchen, MR 
Citation: Abeti R, etal., Brain. 2011 Jun;134(Pt 6):1658-72. doi: 10.1093/brain/awr104.
RGD ID: 10413888
Pubmed: PMID:21616968   (View Abstract at PubMed)
DOI: DOI:10.1093/brain/awr104   (Journal Full-text)

Alzheimer's disease is characterized by beta-amyloid accumulation in the central nervous system. As beta-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 beta-amyloid-induced neuronal death. Exposure of hippocampal neuronal/glial co-cultures to beta-amyloid peptides activates the glial nicotinamide adenine dinucleotide phosphate oxidase, followed by predominantly neuronal cell death. beta-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. beta-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. beta-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 beta-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 beta-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOParp1 (Mus musculus)10413888; 10413888protein:increased activity:brain:RGD 
Alzheimer's disease  IEP 10413888protein:increased activity:brain:RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to amyloid-beta  IMP 10413888protein:increased activity:brain:RGD 
positive regulation of cellular process  IMP 10413888hippocampal neuronsRGD 
positive regulation of mitochondrial depolarization  IMP 10413888protein:increased activity:brain:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Parp1  (poly (ADP-ribose) polymerase 1)

Genes (Mus musculus)
Parp1  (poly (ADP-ribose) polymerase family, member 1)

Genes (Homo sapiens)
PARP1  (poly(ADP-ribose) polymerase 1)


Additional Information