{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:21:02Z","timestamp":1791271262871,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,4,15]]},"abstract":"<jats:p>\n                    Cerebral plaques containing \u03b2-amyloid (\u03b2A4) represent an invariant pathological feature of Alzheimer disease (AD). \u03b2A4 is proteolytically generated from its parent molecule, amyloid precursor protein (APP). In nonneuronal cells \u03b2A4 has been shown to be secreted via a pH-sensitive and endocytosis-dependent pathway, and this process, when occurring in the brain, is considered to play an important role in AD. In neurons the mechanisms of \u03b2A4 production are not known. Here we have analyzed these mechanisms by expressing human APP and its mutant versions in hippocampal neurons using the Semliki forest virus system. We show that these cells initially generate two pools of \u03b2A4, an extracellular and an intracellular, and only the extracellular pool is produced via a pH-sensitive and endocytosis-dependent pathway. Thus, hippocampal neurons are able to utilize an alternate pathway to produce intracellular \u03b2A4. We also show that a common feature of two types of APP mutations (\u201cSwedish\u201d and \u201cLondon\u201d) implicated in early-onset AD is their increased production of C-terminally elongated \u03b2A4 (\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    ), both intra- and extracellularly. Since neurons are the only cells that produce substantial levels of intracellular \u03b2A4 and also the main victims in AD, these findings may provide an important link between \u03b2A4 and neurodegeneration.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.8.4125","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:39Z","timestamp":1027679499000},"page":"4125-4130","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":122,"title":["Intracellular and secreted Alzheimer \u03b2-amyloid species are generated by distinct mechanisms in cultured hippocampal\u2009neurons"],"prefix":"10.1073","volume":"94","author":[{"given":"Pentti J.","family":"Tienari","sequence":"first","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuo","family":"Ida","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Ikonen","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Simons","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Weidemann","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Multhaup","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin L.","family":"Masters","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos G.","family":"Dotti","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology, University of Heidelberg, INF 282, D-69120, Heidelberg, Germany; Cell Biology Programme, European Molecular Biology Laboratories, Meyerhofstrasse 1, D-69012, Heidelberg, Germany; Department of Neurology, University of Helsinki, Haartmaninkatu 4 FIN-00300  Helsinki, Finland; and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, 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