Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease

Annemieke A M Rensink; Henkjan Gellekink; Irene Otte-Höller; Hans J ten Donkelaar; Robert M W de Waal; Marcel M Verbeek; Berry Kremer

doi:10.1007/s00401-002-0585-x

Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease

Acta Neuropathol. 2002 Nov;104(5):525-33. doi: 10.1007/s00401-002-0585-x. Epub 2002 Jul 20.

Authors

Annemieke A M Rensink¹, Henkjan Gellekink, Irene Otte-Höller, Hans J ten Donkelaar, Robert M W de Waal, Marcel M Verbeek, Berry Kremer

Affiliation

¹ Department of Pathology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. a.rensink@pathol.azn.nl

PMID: 12410400
DOI: 10.1007/s00401-002-0585-x

Abstract

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / genetics
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / pharmacology*
Astrocytes / metabolism
Brain / physiology
Cells, Cultured
Cerebral Amyloid Angiopathy, Familial / genetics
Cerebral Amyloid Angiopathy, Familial / metabolism*
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / drug effects
Early Growth Response Protein 1
Female
Gene Expression Profiling
Growth Inhibitors / biosynthesis*
Growth Inhibitors / chemistry
Humans
Immediate-Early Proteins*
In Vitro Techniques
Interleukin-6*
Leukemia Inhibitory Factor
Lymphokines / biosynthesis*
Lymphokines / chemistry
Lymphokines / drug effects
Male
Mutation
Neurofibrillary Tangles / metabolism
Neurons / metabolism
Oligonucleotide Array Sequence Analysis
Peptide Fragments / pharmacology*
Pericytes / chemistry
Pericytes / drug effects*
Somatomedins / biosynthesis*
Somatomedins / chemistry
Somatomedins / drug effects
Transcription Factors / biosynthesis
Transcription Factors / drug effects

Substances

Amyloid beta-Peptides
DNA-Binding Proteins
EGR1 protein, human
Early Growth Response Protein 1
Growth Inhibitors
Immediate-Early Proteins
Interleukin-6
LIF protein, human
Leukemia Inhibitory Factor
Lymphokines
Peptide Fragments
Somatomedins
Transcription Factors
amyloid beta-protein (1-40)