164 NATURE MEDICINE • VOLUME 5 • NUMBER 2 • FEBRUARY 1999 ARTICLES The homologous genes for presenilin 1 (PS1) and presenilin 2 (PS2) encode polytopic transmembrane proteins localized in the nuclear envelope, the endoplasmic reticulum, Golgi apparatus and some as-yet uncharacterized intracytoplasmic vesicles 1–3 . The physiological functions of the presenilins are unknown, but may be related to developmental signaling, apoptotic signal transduction, or processing of selected proteins, including the β-amyloid precursor protein 4–8 (βAPP). Missense mutations in the presenilins are associated with autosomal dominant forms of fa- milial Alzheimer disease 1–3 (FAD). One biochemical effect consis- tently associated with these mutations is an alteration in the proteolytic cleavage of βAPP such that there is overproduction of long-tailed β-amyloid peptide derivatives 9–11 (for example, Aβ 42 ). It has been speculated that this apparently dominant effect of PS1 and PS2 mutations arises either from mistrafficking of βAPP itself (although no direct evidence for this has been found) 12 , or from defective trafficking and/or activation of proteins involved in the proteolytic cleavage of βAPP (ref. 8). Both PS1 and PS2 are components of independent high-mole- cular-weight (≥250 kDa) membrane-bound complexes that are mostly found in the endoplasmic reticulum (ER) and Golgi appa- ratus 13,14 . These presenilin complexes also contain β-catenin and probably other proteins that have not been identified 14,15 . These complexes represent an important functional presenilin moiety that may be affected by presenilin mutations. Most of the prese- nilin proteins (and especially the long-lived endoproteolytic fragments) are contained within these high-molecular-weight protein complexes 13,14 . Moreover, inclusion of mutant monomeric holoproteins and proteolytic fragments into the complexes is required for an effect on Aβ production, and unin- corporated mutant proteolytic fragments are rapidly de- graded 16,17 . Finally, perturbation of interactions between components of multimeric protein complexes is a well-accepted mechanism for both dominant ‘gain of aberrant function’ and dominant ‘loss of function’ effects of disease causing mutations. Thus, the presenilin–β-catenin complexes might be functionally compromised by mutations that cause AD and defects in βAPP processing. Given a putative role for presenilins and their Caenorhabditis elegans homologs in intracellular protein traffick- ing 18 , we have investigated the effects of presenilin mutations on the presenilin–β-catenin interaction by monitoring the intracel- lular trafficking of β-catenin. To achieve this, we have taken ad- vantage of the fact that the intracellular distribution of β-catenin is regulated by activation of the Wnt/β-catenin signal transduc- tion pathway, which can easily be manipulated pharmacologi- cally. Our data show that presenilin mutations associated with Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin,a component of the presenilin protein complex M. NISHIMURA 1 , G. YU 1 , G. LEVESQUE 1 , D.M. ZHANG 1 , L. RUEL 2 , F. CHEN 1 , P. MILMAN 1 , E. HOLMES 1 , Y. LIANG 1 , T. KAWARAI 1 , E. JO 1 , A. SUPALA 1 , E. ROGAEVA 1 , D-M. XU 1 , C. JANUS 1 , L. LEVESQUE 1 , Q. BI 1 , M. DUTHIE 1 , R. ROZMAHEL 3 , K. MATTILA 4 , L. LANNFELT 4 , D. WESTAWAY 1 , H.T.J. MOUNT 1 , J. WOODGETT 2 , P.E. FRASER 1 & P. ST GEORGE-HYSLOP 1 1 Centre for Research in Neurodegenerative Diseases, Departments of Medicine (Neurology), Medical Biophysics, Pathology, and Pharmacology, University of Toronto, 6 Queen’s Park Crescent West, Toronto, Ontario, Canada M5S 3H2; and Department of Medicine (Division of Neurology), The Toronto Hospital, 395 Bathurst Street, Toronto, Ontario, Canada, M5S 3H2 2 Ontario Cancer Institute, Dept of Medical Biophysics and Experimental Therapeutics, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada, M5G 2M9 3 Department of Pharmacology, University of Toronto, and Department of Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto 4 Karolinska Institutet, Department of Clinical Neuroscience and Family Medicine, Novum, KFC, Huddinge Hospital, 141 86 Huddinge, Sweden M.N., G.Y., G.L. & D.M.Z. contributed equally to this study Correspondence should be addressed to P.S.G.-H.; email: p.hyslop@utoronto.ca The presenilin proteins are components of high-molecular-weight protein complexes in the en- doplasmic reticulum and Golgi apparatus that also contain β-catenin. We report here that prese- nilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of β-catenin after activation of the Wnt/β-catenin signal transduction pathway. As with their effect on βAPP processing, the effect of PS1 mutations on trafficking of β-catenin arises from a dominant ‘gain of aberrant function’ activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin–β-catenin protein complexes is central to this process. © 1999 Nature America Inc. • http://medicine.nature.com © 1999 Nature America Inc. • http://medicine.nature.com