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Folia neuropathologica

Alzheimer's disease related peptides affected cholinergic receptor mediated poly(ADP-ribose) polymerase activity in the hippocampus.


PMID 16245207

Abstract

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.

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