{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:12:25Z","timestamp":1791130345885,"version":"4.1.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1996,11,12]]},"abstract":"<jats:p>\n                    Cerebral deposition of the amyloid \u03b2 protein (A\u03b2) is an early\n and invariant feature of Alzheimer disease (AD). Whereas the 40-amino\n acid form of A\u03b2 (A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    ) accounts for \u224890% of all A\u03b2\n normally released from cells, it appears to contribute only to later\n phases of the pathology. In contrast, the longer more amyloidogenic\n 42-residue form (A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    ), accounting for only \u224810% of\n secreted A\u03b2, is deposited in the earliest phase of AD and remains the\n major constituent of most amyloid plaques throughout the disease.\n Moreover, its levels have been shown to be increased in all known forms\n of early-onset familial AD. Thus, inhibition of A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    production is a prime therapeutic goal. The same protease,\n \u03b3-secretase, is assumed to generate the C termini of both\n A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    . Herein, we analyze the\n effect of the compound MDL 28170, previously suggested to inhibit\n \u03b3-secretase, on \u03b2-amyloid precursor protein processing. By\n immunoprecipitating conditioned medium of different cell lines with\n various A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    - and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    -specific antibodies,\n we demonstrate a much stronger inhibition of the \u03b3-secretase cleavage\n at residue 40 than of that at residue 42. These data suggest that\n different proteases generate the A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    and\n A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    C termini. Further, they raise the possibility of\n identifying compounds that do not interfere with general \u03b2-amyloid\n precursor protein metabolism, including A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    production,\n but specifically block the generation of the pathogenic\n A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    peptide.\n                  <\/jats:p>","DOI":"10.1073\/pnas.93.23.13170","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:43:20Z","timestamp":1027680200000},"page":"13170-13175","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":238,"title":["Evidence that the 42- and 40-amino acid forms of amyloid \u03b2 protein are generated from the \u03b2-amyloid precursor protein by different\u2009protease\u2009activities"],"prefix":"10.1073","volume":"93","author":[{"given":"Martin","family":"Citron","sequence":"first","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thekla\u2009S.","family":"Diehl","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Gordon","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja\u2009Leona","family":"Biere","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Seubert","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis\u2009J.","family":"Selkoe","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and\r Harvard Medical School, Boston, MA 02115; and Athena\r Neurosciences Inc., San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1996,11,12]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(88)90673-7"},{"key":"e_1_3_2_2_2","first-page":"122","volume":"58","author":"Castano E M","year":"1988","unstructured":"E M Castano, B Frangione Lab Invest 58, 122\u2013132 (1988).","journal-title":"Lab Invest"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10836"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90458-8"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410370305"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3109\/13506129509031882"},{"key":"e_1_3_2_7_2","first-page":"1257","volume":"148","author":"Mann D M A","year":"1996","unstructured":"D M A Mann, T Iwatsubo, Y Ihara, N J Cairns, P L Lantos, N Bogdanovic, L Lannfelt, B Winblad, M L C Maatschieman, M N 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