TGF-beta(1), regulation of Alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization

The transforming growth factor, TGF-beta(1), has been found to be increased in the central nervous system of Alzheimer's disease (AD) patients, elevat es amyloid precursor protein (APP) mRNA levels in 1 at primary astrocytes, and may initiate or promote the deposition of amyloid-beta (A beta) peptide in AD. Excess APP production in AD, which potentially leads to amyloidogen esis, is in part due to over expression of APP mRNA. The production of APP in a normal human cell line in contrast to transformed or animal cells prov ides a meaningful model to study the regulation of APP gene expression by c ytokines that promotes amyloidogenesis. Here, we report that TGF-beta(1) tr eatment of human astrocytes markedly elevated APP mRNA levels, and also inc reased the half-life of APP message by at least five-fold. Under this condi tion, as detected by mobility shift and UV cross-linking analysis, a novel 68 kDa RNA-protein complex was formed, involving an 81 nucleotide (nt) frag ment within the 3'-untranslated region (UTR), but not the 5'-UTR and coding region of APP mRNA. Insertion of the 3'-UTR onto the chloramphenicol acety l transferase (CAT) mRNA conferred TGF-beta(1) mediated mRNA stability in t ransfected human astrocytes. On the other hand, the same insert carrying a deletion of the APP mRNA cis-element fragment had no effect on CAT mRNA sta bility. A model of APP mRNA regulation is presented in which TGF-beta(1) in duced stabilization of APP message involves the binding activity of a 68 kD a RNA-protein complex within the 3'-UTR, which is likely linked to a reduct ion in the rate of APP mRNA decay. (C) 1999 Elsevier Science B.V. All right s reserved.