Soluble amyloid beta-peptide and myelin basic protein strongly stimulate, alone and in synergism with combined proinflammatory cytokines, the expression of functional nitric oxide synthase-2 in normal adult human astrocytes.
The accumulation of amyloid beta (Abeta)-peptides and their collection in fibrillar plaques in the human brain are believed to be responsible for Alzheimer's disease. The major neuron killers in the Alzheimer brain include proinflammatory cytokines and NO made by NOS-2 (inducible nitric oxide synthase-2). We have determined the effect of a soluble Abeta peptide, Abeta(1-40), on the expression of NOS-2 in astrocytes using a novel model system consisting of pure cultures of cells from adult human brains that, after the first three passages in vitro, become stably locked into the normal astrocytic phenotype like their counterparts in the adult human brain. Abeta(1-40) alone stimulated quiescent astrocytes to start expressing functional NOS-2 and dumping NO into the culture medium during the next 4 days. But adding three of the proinflammatory cytokines commonly produced in the Alzheimer brain--IFN-gamma, IL-1beta, and TNF-alpha--along with Abeta(1-40) more than trebled NOS-2 expression and doubled NO production. In view of the possibility of myelin breakdown in the Alzheimer brain, we also tested the capability of myelin basic protein (MBP) to stimulate NO production using human astrocytes. We found that MBP mimicked the ability of Abeta(1-40) to induce cells to release NO and adding the cytokine triad along with MBP more than doubled NO production and release. Thus, it appears that Abeta peptides and MBP can join forces with proinflammatory cytokines to enhance the NO-mediated killing of neurons in the Alzheimer brain.
Chiarini
Anna
A
Histology and Embryology Unit, Department of Biomedical and Surgical Sciences, University of Verona Medical School, Verona, I-37134, Italy.
Dal Pra
Ilaria
I
Menapace
Lia
L
Pacchiana
Raffaella
R
Whitfield
James F
JF
Armato
Ubaldo
U
D000328:Adult; D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D004676:Myelin Basic Protein / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016207:Cytokines; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D009569:Nitric Oxide