The role of presenilins in Alzheimer's disease.

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In the past few years, 2 homologous polytopic membrane proteins termed presenilins (PSs) have been the focus of several research groups interested in the molecular mechanisms of Alzheimer’s disease (AD). Mutations in the Presenilin 1 (PS1) and Presenilin 2 (PS2) genes account for the majority of the cases of familial earlyonset AD (see the Perspective by Tanzi in the previous issue of the JCI). Analysis of PS1 null mice and other model systems reveals a role for PS1 in development. Furthermore, biochemical and genetic evidence indicate that PS1 plays an important role in facilitating the proteolytic processing of certain proteins, including amyloid precursor protein (APP) and Notch1. Mutant PS proteins influence the γ-secretase‐mediated processing of APP, cause a selective increase in the levels of highly fibrillogenic Aβ42 species, and accelerate Aβ deposition in the brains of transgenic mice. This apparent gain of function of mutant PS in AD seems to be distinct from the role of PS1 in development. Although PS1 interacts with several proteins, including members of the armadillo family of proteins, thus far none of the PS-interacting proteins have been shown to play a direct role in the enhanced production of Aβ42 mediated by mutant PS. This review focuses on the unusual and fascinating aspects of PS metabolism, its role in facilitating the trafficking and cleavage of a set of membrane-bound proteins, and its role in the pathogenesis of AD. The genetics and structure of the presenilins. Approximately 10% of all cases of Alzheimer’s disease (AD) are estimated to be early-onset familial AD (FAD) and show autosomal dominant inheritance. Mutations in the Presenilin 1 (PS1) gene and the related gene Presenilin 2 (PS2), located on chromosomes 14 and 1, respectively, are causative in approximately 50% of pedigrees with FAD. Since 1995, more than 50 different mutations in PS1 have been described in over 80 families of various ethnic origins with early-onset FAD. With 2 notable exceptions (one, a deletion of 30 amino acids, and the other, insertion of 1 amino acid), mutations in presenilins are missense substitutions that result in single amino acid changes. In contrast to PS1 mutations, thus far only 2 mutations in PS2 have been described. These alleles occur in families with variable onset, autosomal dominant FAD. PS1 is a 467‐amino acid polypeptide predicted to contain between 7 and 9 transmembrane-spanning domains and to include a hydrophilic “loop” region. A variety of biochemical and cell biologic approaches were used to determine the topology of PS1 and the Caenorhabditis elegans homologues SEL12 and HOP-1. These data generally predict that the NH2-terminus, the