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Stably transfected cells expressing wild\u2010type human APP (APP<jats:sub>WT<\/jats:sub>) were more resistant to apoptosis\u2010inducing treatments than cells expressing FAD\u2010mutant human APP (APP<jats:sub>FAD<\/jats:sub>). Preventing A\u03b242 production with an M596I mutation (\u03b2\u2013), which blocks \u03b2\u2010secretase cleavage of APP, or by treatment with a \u03b3\u2010secretase inhibitor increased the resistance of APP<jats:sub>FAD<\/jats:sub>\u2010expressing cells to apoptosis. Exposing hAPP<jats:sub>FAD\/\u03b2\u2013<\/jats:sub> cells to exogenous A\u03b242 or conditioned medium from A\u03b242\u2010producing APP<jats:sub>FAD<\/jats:sub> cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most A\u03b2 peptides are generated, by retaining APP in the endoplasmic reticulum (ER)\/intermediate compartment (IC) increased the resistance of APP<jats:sub>FAD<\/jats:sub>\u2010expressing cells to apoptosis and did not alter the resistance of APP<jats:sub>WT<\/jats:sub>\u2010expressing cells. p53\u2010mediated gene transactivation after apoptosis\u2010inducing treatments was much stronger in APP<jats:sub>FAD<\/jats:sub> cells than in hAPP<jats:sub>WT<\/jats:sub> or hAPP<jats:sub>FAD\/\u03b2\u2013<\/jats:sub> cells. In contrast, upon induction of ER stress, cells expressing APP<jats:sub>FAD<\/jats:sub>, hAPP<jats:sub>FAD\/\u03b2\u2013<\/jats:sub>, or APP<jats:sub>WT<\/jats:sub> had comparable levels of glucose\u2010regulated protein\u201078 mRNA, an unfolded protein response indicator. We conclude that A\u03b2, especially intracellular A\u03b2, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53\u2010mediated, and possibly other, proapoptotic pathways.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2004.02816.x","type":"journal-article","created":{"date-parts":[[2004,12,2]],"date-time":"2004-12-02T14:41:32Z","timestamp":1101998492000},"page":"1260-1274","source":"Crossref","is-referenced-by-count":28,"title":["Intracellularly generated amyloid\u2010\u03b2 peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells"],"prefix":"10.1111","volume":"91","author":[{"given":"Luke","family":"Esposito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui\u2010Qiu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Essrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Mucke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,12,2]]},"reference":[{"key":"e_1_2_25_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1998.78.2.547"},{"key":"e_1_2_25_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(03)00117-4"},{"key":"e_1_2_25_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102223200"},{"key":"e_1_2_25_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01273157"},{"key":"e_1_2_25_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-23-09790.1998"},{"key":"e_1_2_25_7_1","doi-asserted-by":"crossref","first-page":"10\u2003539","DOI":"10.1523\/JNEUROSCI.22-24-10539.2002","article-title":"Modulation of Alzheimer\u2010like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid \u03b2 peptides but not on plaque formation","volume":"22","author":"Buttini M.","year":"2002","journal-title":"J. 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