Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the beta peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.

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We have analyzed the modulation of amyloid (3-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.The amyloid A3-protein precursor (APP) gene codes for a family of proteins, each containing a 42-amino acid fragment called amyloid 3 or A4 protein, that is found in brains and the cerebrovasculature of Alzheimer disease, Down syndrome, hereditary cerebral hemorrhage (Dutch type), and aging (1)(2)(3)(4)(5). The APP gene is transcriptionally active in a variety of tissues, highly conserved in evolution, maps to human chromosome 21 (6-10), and probably has no mutations associated with Alzheimer disease (11, 12). Transcripts containing three similar but nonidentical open reading frames have been identified (13)(14)(15)(16)(17). In situ hybridization studies show a very complex pattern of the APP gene expression in brain (18-23).Different levels of APP mRNAs were detected in neurons, some glial cells, and cells that compose blood vessels, presumably some endothelial cells (23). The detection of APP mRNA in these cells strengthens the possibility that at least one form of amyloid 83-protein-cerebrovascular-could originate locally from blood vessels (24, 25).The importance ofunderstanding the regulation ofthe APP gene is underscored by two observations. First, there are differences between Alzheimer disease patients and controls in the levels of APP mRNAs in certain brain regions (19,23,(26)(27)(28)(29)(30). Second, the difference in the level of APP mRNAs between trisomy 21 Down-syndrome patients and controls having two chromosomes 21 was higher than the expected 3:2 ratio (9). In the absence of structural mutations, aberrant levels of the precursor protein may contribute to pathology. These observations suggest that there is aberrant regulation...