Function and Dysfunction of Presenilins in Alzheimer's Disease

S.S. Sisodia

The Department of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, Il. 60637, USA

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Autosomal dominant inheritance of mutations in genes on chromosomes 14 and 1, encoding presenilins (PS1 and PS2, respectively) are causative in the vast majority of pedigrees with familial Alzheimer's disease (FAD). Biochemical studies have confirmed that PS are ubiquitously expressed, polytopic membrane proteins that areendoproteolytically processed in vivo; the PS derivatives coassemble in heteromeric complexes that accumulate in a saturable and stoichiometric manner. A PS homologue in C. elegans, termed sel-12, facilitates lin-12/Notch signalling during developent; in worms, human PS complements deficiencies caused by loss of sel-12. The function of PS1 in vertebrate development has been revealed by analysis of mice with inactivated PS1 alleles (PS1-/-); these animals die before birth, and exhibit axial skeletal deficits and cerebral hemorrhages. In mid-gestation PS1-/- embryos, somite segmentation is disrupted, and expression of Notch 1 and Dll1 mRNAs are abolished in the presomitic mesoderm. The developmental phenotypes of PS1-/- embryos can be rescued with transgenes encoding either wild-type or FAD-linked A246E human PS1, arguing that FAD-linked mutant PS1 retain normal function during embryonic development. The mechanism(s) by which mutant PS cause AD are not fully clarified, but expression of FAD-linked PS1 leads to elevated production of Ab42 peptides and acceleration of Ab deposition in brains of transgenic mice. Remarkably, studies of primary cultures from PS1-/- mice reveal that PS1 enhances APPsa secretion coincident with inhibited Ab secretion. While these studies directly implicate PS1 in the regulation of APP/Ab metabolism, evidence is emerging that PS1 plays a more general role in secretory trafficking and metabolism. Future efforts aimed at identifying molecules which facilitate PS1 function will be critical for understanding the role of PS1 in the secretory/endocytic apparatus in normal and pathogenic settings.