Biology and genetics of the presenilin proteins associated with alzheimer disease

Mutations in the presenilin 1 (PS1) and the homologous presenilin 2 (PS2) genes are associated with early onset familial Alzheimer Disease. We have cloned a homologue from D. melanogaster. Analysis of the genomic structure of the human PS! gene shows that there are 13 exons. The predominant transcript in brain begins at Exon 1 downstream of a TATA box and multiple STAT elements. In non-neurologic tissues some transcripts begin at an alternate initial exon, Exon 2, downstream of a GC-rich sequence. Transcripts beginning at Exon 1 splice directly to Exon 3. Exon 9 encodes residues at the beginning of the TM6-TM7 loop, and undergoes alternative splicing in leukocytes but not brain. Immunocytochemlstry shows that PS1 and PS2 are mainly in intracellular membranes. Differential solubilization with digitonin shows that the N-terminus and the TM6-TM7 loop are cytoplasmic, while the TM1-TM2 loop is intraluminal. The function of wild type or mutant PS1 and PS2 is unknown. A role in protein and membrane trafficking is compatible with studies in transfected cells and transgenic animals which show that PS1 mutations cause mismetabolism of P APR and overproduction of Aβ₄₂, but do not alter α- and β- secretase activity. Similar quantitative changes occur in human post-mortem brain tissue.