Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.
Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD.
Kelly
J F
JF
Molecular Physiology and Genetics Section, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA.
Furukawa
K
K
Barger
S W
SW
Rengen
M R
MR
Mark
R J
RJ
Blanc
E M
EM
Roth
G S
GS
Mattson
M P
MP
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D007295:Inositol Phosphates; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011976:Receptors, Muscarinic; C098994:amyloid beta-protein (1-43); D002217:Carbachol; D020558:GTP Phosphohydrolases; D002118:Calcium