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

Amyloid-beta (Aalpha) 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 DAalpha(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.