{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:22:19Z","timestamp":1791231739698,"version":"4.1.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"48","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:p>\n                    One of the neuropathological hallmarks of Alzheimer's disease (AD) is the amyloid plaque, primarily composed of aggregated amyloid-beta (A\u03b2) peptide. In vitro, A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    , the major alloform of A\u03b2 found in plaques, self-assembles into fibrils at micromolar concentrations and acidic pH. Such conditions do not exist in the extracellular fluid of the brain where the pH is neutral and A\u03b2 concentrations are in the nanomolar range. Here, we show that extracellular soluble A\u03b2 (sA\u03b2) at concentrations as low as 1 nM was taken up by murine cortical neurons and neuroblastoma (SHSY5Y) cells but not by human embryonic kidney (HEK293) cells. Following uptake, A\u03b2 accumulated in Lysotracker-positive acidic vesicles (likely late endosomes or lysosomes) where effective concentrations (&gt;2.5 \u03bcM) were greater than two orders of magnitude higher than that in the extracellular fluid (25 nM), as quantified by fluorescence intensity using laser scanning confocal microscopy. Furthermore, SHSY5Y cells incubated with 1 \u03bcM A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    for several days demonstrated a time-dependent increase in intracellular high molecular weight (HMW) (&gt;200 kDa) aggregates, which were absent in cells grown in the presence of A\u03b2\n                    <jats:sub>1\u201340<\/jats:sub>\n                    . Homogenates from these A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    -loaded cells were capable of seeding amyloid fibril growth. These results demonstrate that A\u03b2 can be taken up by certain cells at low physiologically relevant concentrations of extracellular A\u03b2, and then concentrated into endosomes\/lysosomes. At high concentrations, vesicular A\u03b2 aggregates to form HMW species which are capable of seeding amyloid fibril growth. We speculate that extrusion of these aggregates may seed extracellular amyloid plaque formation during AD pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0911281106","type":"journal-article","created":{"date-parts":[[2009,11,12]],"date-time":"2009-11-12T22:17:50Z","timestamp":1258064270000},"page":"20324-20329","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":404,"title":["Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide"],"prefix":"10.1073","volume":"106","author":[{"given":"Xiaoyan","family":"Hu","sequence":"first","affiliation":[{"name":"Hope Center for Neurological Disorders and Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott L.","family":"Crick","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Center for Computational Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Frieden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit V.","family":"Pappu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Center for Computational Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Moo","family":"Lee","sequence":"additional","affiliation":[{"name":"Hope Center for Neurological Disorders and Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(84)80190-4"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00463a003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(94)80591-0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1992.tb27476.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/416535a"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-26-08844.2003"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.10.028"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/359325a0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.55.7.937"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.56.6.673"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000046581.81650.D0"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2006.100529"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.15.7942"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9904149"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2006.02.006"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.02.009"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-007-0237-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmr.699"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.6.2313"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.1999.0816"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69062452.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90165-1"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.02.002"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.66.1.385"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.16.7437"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.51.32916"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2085-06.2006"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005698200"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1161591"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0341410"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)48529-8"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)01279-2"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)01876-6"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00434-3"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64700-1"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2168"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.5858\/2001-125-0489-IAAPDO"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1515\/REVNEURO.2005.16.2.123"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.07.017"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604436200"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20149"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3140701"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.07.027"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2007.29"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.7.1744"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0911281106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:06:00Z","timestamp":1649790360000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0911281106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":45,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["10.1073\/pnas.0911281106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0911281106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12]]},"assertion":[{"value":"2009-04-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-12-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}