The role of macrophage migration inhibitory factor in Alzheimer's disease.
Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.
Bacher
Michael
M
Department of Neurology, Philipps-University Marburg, Germany.
Deuster
Oliver
O
Aljabari
Bayan
B
Egensperger
Rupert
R
Neff
Frauke
F
Jessen
Frank
F
Popp
Julius
J
Noelker
Carmen
C
Reese
Jens Peter
JP
Al-Abed
Yousef
Y
Dodel
Richard
R
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human