Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: reversal by NMDA receptor blockade.
Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex. In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells. In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid(1-42) or beta-amyloid(25-35) infusion into the rat nucleus basalis. The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity. We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.
O'Mahony
S
S
Department of Pharmacology, University College Galway, Ireland.
Harkany
T
T
Rensink
A A
AA
Abrahám
I
I
De Jong
G I
GI
Varga
J L
JL
Zarándi
M
M
Penke
B
B
Nyakas
C
C
Luiten
P G
PG
Leonard
B E
BE
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D002802:Cholinesterases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017764:Parasympathectomy; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D002802:Cholinesterases; C010739:ifenprodil