Non A beta component of Alzheimer's disease amyloid and amyloid beta peptides evoked poly(ADP-ribose) polymerase-dependent release of apoptosis-inducing factor from rat brain mitochondria.
Amyloid beta peptide (A beta) and non-A beta component of Alzheimer's disease amyloid (NAC) are involved in pathomechanism of Alzheimer's Disease (AD) and are deposited in the AD brain in the form of senile plaques. However, the mechanism of their neurotoxicity is not fully understood. In this study the sequence of events involved in NAC and A beta peptides evoked toxicity was investigated in brain slices, synaptosomes and in subcellular fractions. Radio-, immunochemical, spectrophotometrical methods and DNA electrophoresis were used in this study. Our data indicated that A beta 1-40 (25 microM) and NAC (10 microM) peptides induced liberation of free radicals and massive DNA damage that lead to activation of DNA bound enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In consequence of these processes apoptosis-inducing factor (AIF) was released from mitochondria and was translocated to nucleus. The inhibitor of PARP, 3-aminobenzamide significantly decreased AIF release from mitochondria and its translocation. Both peptides under the investigational conditions had no effect on caspase-3 activity. Our data indicated that A beta and NAC peptides stimulate AIF-dependent apoptotic pathway that seems to be caspase independent process. The inhibition of PARP-1 may protect the brain against A beta and NAC toxicity.
Adamczyk
A
A
Department of Cellular Signalling, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. agatazambrzycka@hotmail.com
Czapski
G A
GA
Jeśko
H
H
Strosznajder
R P
RP
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
C494831:Aifm1 protein, rat; D016229:Amyloid beta-Peptides; D051033:Apoptosis Inducing Factor; D001549:Benzamides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C497606:Snca protein, rat; D051844:alpha-Synuclein; C025160:3-aminobenzamide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3