Alzheimer\'s disease related peptides affected cholinergic receptor mediated poly(ADP-ribose) polymerase activity in the hippocampus
Journal Title: Folia Neuropathologica - Year 2005, Vol 43, Issue 3
Abstract
Our previous studies indicated that Alzheimer's disease (AD) related amyloid beta peptide (Aβ) 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 Aβ 25-35 (25 µM) and non-Aβ component of Alzheimer's disease amyloid (NAC, 10 µM) 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 µM) 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 Aβ and NAC peptide. These toxic peptides themselves significantly stimulated PARP-1 activity by free radicals mediated DNA damage. These data indicated that Aβ and NAC peptide affected mChR-dependent signal transduction to PARP-1 probably through free radicals evoked inhibition of IP3 formation by phospholipase C.
Authors and Affiliations
Agata Adamczyk, Henryk Jęśko, Robert Strosznajder
Keywords
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