Differential effects of transforming growth factor-beta s and glial cell line-derived neurotrophic factor on gene expression of presenilin-1 in humanpost-mitotic neurons and astrocytes

Mutations in the presenilin-1 gene are linked to the majority of early-onse t familial Alzheimer's disease cases. We have previously shown that the exp ression of transforming growth factor-beta is altered in Alzheimer's patien ts, compared to controls. Here we examine presenilin-1 expression in human post-mitotic neurons (hNT cells), normal human astrocytes, and human brain tumor cell lines following treatment with three isoforms of transforming gr owth factor-beta, or glial cell line-derived neurotrophic factor, a member of the transforming growth factor-beta superfamily. As the NT2/D1 teratocar cinoma cell line is treated with retinoic acid to induce differentiation to hNT cells, presenilin-1 messenger RNA expression is dramatically increased . Furthermore, there is a 2-3-fold increase in presenilin-1 messenger RNA e xpression following treatment of hNT cells with growth factors and similar results are found by Western blotting and with immunohistochemical staining for presenilin-1 protein. However, treatment of normal human astrocytes wi th cytokines results in minimal changes in presenilin-1 messenger RNA and p rotein, interestingly, the expression of presenilin-1 in human U87 MG astro cytoma and human SK-N-SH neuroblastoma cells is only increased when cells a re treated with glial cell line-derived neurotrophic factor or transforming growth factor-beta 3. These findings suggest that endogenous presenilin-1 gene expression in huma n neurons can be induced by growth factors present in normal and diseased b rain tissue. Cytokines may play a major role in regulating expression of pr esenilin-1 which may affect its biological actions in physiological and pat hological conditions. (C) 1999 IBRO. Published by Elsevier Science Ltd.