Neuroglobin attenuates beta-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo.
Neuroglobin (Ngb), a vertebrate globin expressed primarily in neurons, is induced by and protects against neuronal hypoxia and cerebral ischemia. To investigate the spectrum and mechanism of Ngb's neuroprotective action, we studied the effect of transgenic overexpression of Ngb on NMDA and beta-amyloid (Abeta) toxicity in murine cortical neuron cultures in vitro and on the phenotype of Alzheimer's disease (AD) transgenic (APP(Sw,Ind)) mice. Compared with cortical neuron cultures from wild-type mice, cultures from Ngb-overexpressing transgenic (Ngb-Tg mice) were resistant to the toxic effects of NMDA and Abeta(25-35), as measured by polarization of cell membrane lipid rafts, mitochondrial aggregation, lactate dehydrogenase release, and nuclear fragmentation. In addition, compared with APP(Sw,Ind) mice, double-transgenic (Ngb-Tg x APP(Sw,Ind)) mice showed reductions in thioflavin-S-stained extracellular Abeta deposits, decreased levels of Abeta(1-40) and Abeta(1-42), and improved behavioral performance in a Y-maze test of spontaneous alternations. These findings suggest that the spectrum of Ngb's neuroprotective action extends beyond hypoxic-ischemic insults. Ngb may protect neurons from NMDA and Abeta toxicity by inhibiting the formation of a death-signaling membrane complex, and interventions that increase Ngb expression could have therapeutic application in AD and other neurodegenerative disorders.
Khan
Adil A
AA
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA. akhan@buckinstitute.org
Mao
Xiao Ou
XO
Banwait
Surita
S
Jin
Kunlin
K
Greenberg
David A
DA
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000633:toxicity; D000818:Animals; D001923:Brain Chemistry; D002478:Cells, Cultured / Q000473:pathology; D003433:Crosses, Genetic; D005914:Globins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018782:Maze Learning; D021962:Membrane Microdomains / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D000078787:Neuroglobin; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology / Q000633:toxicity; D016037:Single-Blind Method
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005914:Globins