Alzheimer's disease related peptides affected cholinergic receptor mediated poly(ADP-ribose) polymerase activity in the hippocampus.
Our previous studies indicated that Alzheimer's disease (AD) related amyloid beta peptide (Abeta) significantly altered muscarinic cholinergic receptor (mChR) signaling on the level of G protein regulated phospholipase C (PLC) leading to the lower formation of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Recent studies indicated that poly (ADP-ribose) polymerase-1 (PARP-1) is a new nuclear target in signal transduction pathway in the brain. In this study the effect of Abeta 25-35 (25 microM) and non-Abeta component of Alzheimer's disease amyloid (NAC, 10 microM) on mChR-dependent signaling to PARP-1 was determined. PARP-1 activity was estimated radiochemically using egzogenous substrate adenine[14C]NAD. The results showed that the non hydrolysable agonist of mChR, carbachol (1 mM) together with GTP(g)S (100 microM) stimulated PARP-1 activity in the hippocampus by about 100%. TMB-8, inhibitor of IP3 receptor decreased PARP-1 activation evoked by carbachol/GTP(g)S. Stimulation of mChR did not lead to free radicals generation but activate PARP-1 through IP3/Ca2+ regulated processes. This cholinergic receptor dependent PARP-1 activation was abolished by Abeta and NAC peptide. These toxic peptides themselves significantly stimulated PARP-1 activity by free radicals mediated DNA damage. These data indicated that Abeta and NAC peptide affected mChR-dependent signal transduction to PARP-1 probably through free radicals evoked inhibition of IP3 formation by phospholipase C.
Adamczyk
Agata
A
Department of Cellular Signaling, Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland. agatazambrzycka@hotmail.com
Jeśko
Henryk
H
Strosznajder
Robert Piotr
RP
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018679:Cholinergic Agonists; D005609:Free Radicals; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D002217:Carbachol; D011065:Poly(ADP-ribose) Polymerases