Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage.
Glia maturation factor (GMF), discovered and characterized in our laboratory, is a highly conserved protein primarily localized in mammalian central nervous system. Previously we demonstrated that GMF is required in the induced production of proinflammatory cytokines and chemokines in brain cells. We now report that ventricular infusion of human amyloid beta peptide1-42 (Abeta1-42) in mouse brain caused glial activation and large increases in the levels of GMF as well as induction of inflammatory cytokine/chemokine known for launching the neuro inflammatory cascade in Alzheimer's disease (AD). To test the hypothesis that GMF is involved in the pathogenesis of AD, we infused Abeta1-42 in the brain of GMF-deficient (GMF-KO) mice, recently prepared in our laboratory. GMF-deficient mice showed reduced glial activation and significantly suppressed proinflammatory cytokine/chemokine production following Abeta infusion compared to wild type (Wt) mice. The decrease in glial activation in the GMF-KO mice is also associated with significant reduction in Abeta induced loss of pre-synaptic marker, synaptophysin, and post-synaptic density protein-95 (PSD 95). We also examined the potential relationship between GMF or lack of it with learning and memory using the T-maze, Y-maze, and water maze, hippocampal-dependent spatial memory tasks. Our results show that memory retention was improved in GMF-KO mice compared to Wt controls following Abeta infusion. Diminution of these Abeta1-42 effects in primary cultures of GMF-KO astrocyte and microglia were reversed by reconstituted expression of GMF. Taken together, our results indicate a novel mediatory role of GMF in the neuro-inflammatory pathway of Abeta and its pro-inflammatory functions.
Zaheer
Asgar
A
Veterans Affair Medical Center, and Division of Neurochemistry and Neurobiology, Department of Neurology, University of Iowa, Iowa City, IA 52242, USA. asgar-zaheer@uiowa.edu
Zaheer
Smita
S
Thangavel
Ramasamy
R
Wu
Yanghong
Y
Sahu
Shailendra K
SK
Yang
Baoli
B
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020904:Glia Maturation Factor / Q000172:deficiency / Q000494:pharmacology*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016207:Cytokines; D020904:Glia Maturation Factor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)