{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:15:40Z","timestamp":1792048540317,"version":"4.4.0"},"reference-count":30,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5530","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2001,7,27]]},"abstract":"<jats:p>\n            The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly\n            <jats:italic>Drosophila melanogaster<\/jats:italic>\n            . Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.\n          <\/jats:p>","DOI":"10.1126\/science.1062382","type":"journal-article","created":{"date-parts":[[2006,3,28]],"date-time":"2006-03-28T18:37:53Z","timestamp":1143571073000},"page":"711-714","source":"Crossref","is-referenced-by-count":855,"title":["Tauopathy in\n            <i>Drosophila<\/i>\n            : Neurodegeneration Without Neurofibrillary Tangles"],"prefix":"10.1126","volume":"293","author":[{"given":"Curtis W.","family":"Wittmann","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew F.","family":"Wszolek","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Shulman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Salvaterra","sequence":"additional","affiliation":[{"name":"Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jada","family":"Lewis","sequence":"additional","affiliation":[{"name":"Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Hutton","sequence":"additional","affiliation":[{"name":"Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mel B.","family":"Feany","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06906.x"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410400204"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.118.2.401"},{"key":"e_1_3_1_6_2","unstructured":"Heads from adult flies at 1 day after eclosion were fixed in formalin and embedded in paraffin and 4-\u03bcm frontal sections were prepared. Serial sections were cut through the entire brain placed on a single glass slide and stained with hematoxylin and eosin (H&E) Bielschowsky (Fig. 2 A and B) or bodian silver stains. H&E sections highlight the normal arrangement of basophilic neuronal and glial cell bodies in the outer cortical layer and the inner eosinophilic neuropil regions. Silver stains label axonal projections and demonstrate anatomic features. The quantitative analysis in Fig. 2E was performed on 4-\u03bcm-thick paraffin sections stained with H&E. The number of degenerating neurons and the number of vacuoles measuring greater than 5 \u03bcm in diameter were counted in five well-oriented frontal sections between the level of the fan-shaped body and the calyx of the mushroom body. Sections from at least five individual brains were examined per time point for each genotype."},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65272-8"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81127-7"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/78078"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.3109\/01677068609106845"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90200-B"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-19-07425.1997"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19970415)48:2<128::AID-JNR5>3.0.CO;2-E"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0029(19990415)45:2<65::AID-JEMT2>3.0.CO;2-0"},{"key":"e_1_3_1_15_2","unstructured":"Sarcosyl insoluble tau was prepared by standard methods (15 16). Briefly fly heads were homogenized in 10 volumes buffer and centrifuged for 20 min at 15 000 g. The supernatant was brought to 1% N -lauroylsarcosinate incubated for 1 hour at room temperature with shaking and then further centrifuged for 1 hour at 100 000 g. The resultant high-speed pellet was resuspended at 10 \u03bcl per 50 mg of starting material. Tau was detected by immunoblot analysis in the sarcosyl insoluble fraction and this sarcosyl insoluble fraction was subjected to immunoelectron microscopy. Control genotype: elav-GAL4\/ +. Experimental genotypes: elav-GAL4\/+; UAS-wt tau\/+ elav-GAL4\/+; UAS-R406W tau\/+ and elav-GAL4\/UAS-V337M tau\/+. All flies were 30 days old."},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.15.5827"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(92)90117-V"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/116.1.281"},{"key":"e_1_3_1_19_2","unstructured":"For analysis of specific neuronal subsets we expressed wild-type and mutant tau using Cha-GAL4 for cholinergic neurons and D42-GAL4 for motor neurons. The D42-GAL4 and Cha - GAL4 lines produced equivalent amounts of \u03b2-galactosidase (\u03b2-Gal) when crossed to a GAL4 responsive \u03b2-Gal transgene ( UAS-lacZ ). A transgene encoding a marker protein ( UAS-lacZ or UAS-GFP ) was coexpressed to provide an independent method of identifying cholinergic or motor neurons. Cholinergic neurons in the optic lamina were immunostained for AT8 \u03b2-Gal or green fluorescent protein (GFP) and the number of immunoreactive neurons per 60-\u03bcm region of optic lamina (4-\u03bcm-thick sections) was counted. Each time point and genotype represents the average of at least six separate retinas. For analysis of process staining with acetylcholine or tyrosine hydroxylase immunohistochemistry in panneural expressing flies ( elav-GAL4 ) sections of control and transgenic fly brains were prepared and immunostained in parallel. Similar results were seen in at least three separate experiments."},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/35006074"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.15.7036"},{"key":"e_1_3_1_22_2","unstructured":"See supplementary data available at Science Online at www.sciencemag.org\/cgi\/content\/full\/1062382\/DC1."},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63997-1"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.9.4733"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19990315)55:6<713::AID-JNR6>3.0.CO;2-G"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/122.4.741"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/70532"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/35040584"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.23.1.217"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/59.10.847"},{"key":"e_1_3_1_31_2","unstructured":"We thank W. Bender for generous support P. Davies and P. Seubert for valuable reagents and H. Shing D. Bowman M. Slaney C. Ridolfi and A. Merola for excellent technical assistance. This work was funded by grants from the National Institute on Aging the Howard Hughes Medical Institute the McKnight Endowment Fund for Neuroscience (M.B.F.) and the NIH (W. Bender)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1062382","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T22:11:44Z","timestamp":1704838304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1062382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,7,27]]},"references-count":30,"journal-issue":{"issue":"5530","published-print":{"date-parts":[[2001,7,27]]}},"alternative-id":["10.1126\/science.1062382"],"URL":"https:\/\/doi.org\/10.1126\/science.1062382","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,7,27]]}}}