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Mutations in the human presenilin genes (PSEN1 and PSEN2) are associated with early onset familial Alzheimer disease. The presenilin genes encode integral membrane proteins with similar structures, which suggests that they may have closely related, but as yet unknown functions. Analysis of the 5' upstream sequence and the structure of the PSEN1 gene reveals that the 5' sequence contains multiple putative transcription regulatory elements including clusters of STAT elements involved in transcriptional activation in response to signal transduction. The first four exons contain untranslated sequences, with Exons 1 and 2 representing alternate initial transcription sites. The function of these alternate initial exons is unclear. Exon 4 bears the first ATG sequence. The last 12 bp of Exon 4 is used as an alternative splice donor site. Exon 9 is alternately spliced in leukocytes, but not in most other tissues. Splicing of Exon 9 is predicted to cause significant structural changes to the protein. The majority of transcripts expressed in most tissues are polyadenylated 1127 bp from the TAG stop codon in Exon 13. A small proportion of transcripts contain the same 5'UTR and ORF but are polyadenylated 4435 bp from the stop codon. The longer polyadenylated transcripts contain three additional palindromes and at least one additional stem-loop structure with stabilities greater than -16 kcal/mol.

The human beta-amyloid protein precursor (beta-APP) gene (symbol APP) shows variable levels of expression in different human tissues, including brain. Because at least a moderate level of beta-APP expression is probably a necessary, although not sufficient, condition for diseases associated with pathologic deposition of beta-APP proteolytic products (such as the A beta peptide), we sought to identify factors in the 5' promoter of the human APP gene that may regulate tissue-specific expression of the APP gene. We report that sequences upstream from -500 bp in the APP promoter display complex, tissue-specific patterns of methylation. Furthermore, different patterns of methylation were observed even in DNA from different regions of brain. These differentially methylated sequences are able to bind nuclear proteins expressed in brain and HeLa cells and are also methylated in neocortex of nonhuman primates. Because these methylation patterns crudely reflect differences in APP expression, they may represent one mechanism for the tissue-specific regulation of APP expression.