{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:34:03Z","timestamp":1791246843730,"version":"4.1.0"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,12,4]]},"abstract":"<jats:p>\n                    Memory impairment progressing to dementia is the main\n clinical symptom of Alzheimer's disease (AD). AD is characterized\n histologically by the presence of \u03b2-amyloid (A\u03b2) plaques and\n neurofibrillary tangles in specific brain regions. Although A\u03b2\n derived from the A\u03b2 precursor protein (\u03b2-APP) is believed to play a\n central etiological role in AD, it is not clear whether soluble\n and\/or fibrillar forms are responsible for the memory deficit. We\n have generated and previously described mice expressing human wild-type\n \u03b2-APP\n                    <jats:sub>751<\/jats:sub>\n                    isoform in neurons. These transgenic mice\n recapitulate early histopathological features of AD and form A\u03b2\n deposits but no plaques. Here we describe a specific and progressive\n learning and memory impairment in these animals. In the Morris water\n maze, a spatial memory task sensitive to hippocampal damage, one\n pedigree already showed significant differences in acquisition in\n 3-month-old mice that increased in severity with age and were expressed\n clearly in 6-month- and 2-year-old animals. The second transgenic\n pedigree displayed a milder impairment with a later age of onset.\n Performance deficits significantly decreased during the 6 days of\n training in young but not in aged transgenic animals. Both pedigrees of\n the transgenic mice differed from wild-type mice by less expressed\n increase of escape latencies after the platform position had been\n changed in the reversal experiment and by failure to prefer the goal\n quadrant in probe trials. Both pedigrees performed at wild-type level\n in a number of other tests (open field exploration and passive and\n active place avoidance). The results suggest that plaque formation is\n not a necessary condition for the neuronal \u03b2-APP\n                    <jats:sub>751<\/jats:sub>\n                    transgene-induced memory impairment, which may be caused by \u03b2-APP\n overexpression, isoform misexpression, or elevated soluble A\u03b2.\n                  <\/jats:p>","DOI":"10.1073\/pnas.261562998","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:07Z","timestamp":1027679707000},"page":"14675-14680","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["Specific spatial learning deficits become severe with age in \u03b2-amyloid precursor protein transgenic mice that harbor diffuse \u03b2-amyloid deposits but do not form plaques"],"prefix":"10.1073","volume":"98","author":[{"given":"Milla","family":"Koistinaho","sequence":"first","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ort","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Cimadevilla","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Vondrous","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Cordell","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jari","family":"Koistinaho","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Bures","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda S.","family":"Higgins","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Academy of Sciences of the Czech\r Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;\r A. I. Virtanen Institute for Molecular Sciences,\r University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland;\r Department of Psychiatry, First School of Medicine,\r Charles University, Ke Karlovu 2, 128 08 Prague 2, Czech Republic;\r Department of Experimental Psychology and\r Psychobiology, Universidad de Almer\u00eda, Carretera de\r Sacramento s\/n, 04120 Almer\u00eda, Spain; Scios,\r Inc..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,11,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/399a023"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03540340059034"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90315-I"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(92)90228-6"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90096-2"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.63020781.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00125-2"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.13-04-01676.1993"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3109\/13506129809007283"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(92)90055-3"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.25.12243"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-20-08876.1999"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5284.99"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0197-0186(95)00067-I"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1054\/mehy.2000.1212"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1037\/0735-7044.113.5.982"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/35050110"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/35050116"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0958-1669(98)80132-8"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.32.1.461"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-4310(99)01465-3"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(00)00033-8"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/352239a0"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410350514"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.10.4402"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90166-3"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687256"},{"key":"e_1_3_3_28_2","first-page":"457","volume":"73","author":"Burger 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of the National Academy of 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