{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:52:33Z","timestamp":1790970753818,"version":"4.1.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,3,4]]},"abstract":"<jats:p>To gain insights into the significance of presenilins (PS) in the pathogenetic mechanisms of early-onset familial Alzheimer disease (FAD), we expressed cDNAs for wild-type PS2 and PS2 with the Volga German (N141I) mutation in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid \u03b2 protein (A\u03b2). PS2 was identified as a 50- to 55-kDa protein, which was cleaved to produce N-terminal fragments of 35\u201340 kDa and C-terminal fragments of 19\u201323 kDa. The Volga German (N141I) mutation did not cause any significant change in the metabolism of PS2. COS-1 cells doubly transfected with cDNAs for N141I mutant PS2 and human \u03b2-amyloid precursor protein (\u03b2APP) or a C-terminal fragment thereof, as well as mouse Neuro2a neuroblastoma cells stably transfected with N141I mutant PS2 alone, secreted 1.5- to 10-fold more A\u03b2 ending at residues 42 (or 43) [A\u03b242(43)] compared with those expressing the wild-type PS2. These results strongly suggest that the PS2 mutation (N141I) linked to FAD alters the metabolism of A\u03b2\/\u03b2APP to foster the production of the form of A\u03b2 that most readily deposits in amyloid plaques. Thus, mutant PS2 may lead to AD by altering the metabolism of A\u03b2\/\u03b2APP.<\/jats:p>","DOI":"10.1073\/pnas.94.5.2025","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:43:20Z","timestamp":1027680200000},"page":"2025-2030","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":329,"title":["The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid \u03b2 protein ending at the 42nd (or 43rd) residue"],"prefix":"10.1073","volume":"94","author":[{"given":"Taisuke","family":"Tomita","sequence":"first","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kume","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohki","family":"Shinozaki","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Tokuhiro","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Capell","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Walter","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Gr\u00fcnberg","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Haass","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Iwatsubo","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiko","family":"Obata","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,3,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.31.18295"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.19.8552"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/349704a0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0892-345"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/360672a0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8424174"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8191290"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00069a001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1292-330"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/375754a0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0296-224"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.17.9223"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401652"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-219"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80232-9"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0995-848a"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199512000-00071"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7638621"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7638622"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/376775a0"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80291-3"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-864"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.2.488"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.1280"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/347566a0"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36599-7"},{"key":"e_1_3_3_27_2","first-page":"1517","volume":"148","author":"Iwatsubo T","year":"1996","unstructured":"T Iwatsubo, H Yamaguchi, M Fujimuro, H Yokosawa, Y Ihara, J Q Trojanowski, V M-Y Lee Am J Pathol 148, 1517\u20131529 (1996).","journal-title":"Am J Pathol"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90458-8"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00032a022"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80230-5"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/383710a0"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410400205"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410410110"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.94.5.2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T14:16:39Z","timestamp":1649859399000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.94.5.2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,3,4]]},"references-count":33,"journal-issue":{"issue":"5","published-print":{"date-parts":[[1997,3,4]]}},"alternative-id":["10.1073\/pnas.94.5.2025"],"URL":"https:\/\/doi.org\/10.1073\/pnas.94.5.2025","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,3,4]]},"assertion":[{"value":"1996-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1996-12-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1997-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}