Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease.
Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA expression array was performed to detect differential gene expression of Abeta-treated versus untreated HBP. Messenger RNA expression of leukemia inhibitory factor (LIF) and insulin-like growth factor binding protein 3 (IGFBP-3) was increased in DAbeta(1-40)-treated HBP, whereas early growth response factor-1 (Egr-1) expression was decreased. Corresponding protein expression was investigated in AD and control brains. In all AD cases examined, LIF expression was observed in senile plaques and cerebral amyloid angiopathy, whereas IGFBP-3 expression in these lesions was only observed in a subset of cases. LIF and IGFBP-3 were also expressed in neurofibrillary tangles, as well as in neurons in AD and control brains. Egr-1 was predominantly expressed in astrocytes. Given its known involvement in both neuronal and immune responses to injury, the cytokine LIF may be a mediator of the inflammatory reaction seen in AD. IGFBP-3 is known to inhibit cell proliferation and induce apoptosis and may therefore contribute to neuronal degeneration in AD.
Rensink
Annemieke A M
AA
Department of Pathology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. a.rensink@pathol.azn.nl
Gellekink
Henkjan
H
Otte-Höller
Irene
I
ten Donkelaar
Hans J
HJ
de Waal
Robert M W
RM
Verbeek
Marcel M
MM
Kremer
Berry
B
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000502:physiology; D002478:Cells, Cultured; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects; D051766:Early Growth Response Protein 1; D005260:Female; D020869:Gene Expression Profiling; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D017874:Immediate-Early Proteins; D066298:In Vitro Techniques; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000096:biosynthesis* / Q000737:chemistry / Q000187:drug effects; D008297:Male; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000494:pharmacology*; D020286:Pericytes / Q000737:chemistry / Q000187:drug effects*; D013002:Somatomedins / Q000096:biosynthesis* / Q000737:chemistry / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006131:Growth Inhibitors; D017874:Immediate-Early Proteins; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D010446:Peptide Fragments; D013002:Somatomedins; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40)