Activation of PARP by oxidative stress induced by β-amyloid: implications for Alzheimer's disease.
Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterised by progressive cognitive impairment, dementia and atrophy of the central nervous system. The pathological hallmarks include the accumulation of the peptide β-amyloid (Aβ) which itself is toxic to neurons in culture. Recently, it has been discovered that Aβ activates the protein poly(ADP-ribosyl) polymerase-1 (PARP-1) specifically in astrocytes, leading indirectly to neuronal cell death. PARP-1 is a DNA repair enzyme, normally activated by single strand breaks associated with oxidative stress, which catalyses the formation of poly ADP-ribose polymers from nicotinamide adenine dinucleotide (NAD(+)). The pathological over activation of PARP-1 causes depletion of NAD(+) and leads to cell death. Here we review the relationship between AD and PARP-1, and explore the role played by astrocytes in neuronal death. AD has so far proven refractory to any effective treatment. Identification of these pathways represents a step towards a greater understanding of the pathophysiology of this devastating disease with the potential to explore novel therapeutic targets.
Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK. r.abeti@ucl.ac.uk
Rosella
R
Abeti
Michael R
MR
Duchen
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases