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In the present study, we analyzed proteomic changes in synaptosomal fractions from Tg2576 mice that overexpress mutant human amyloid precursor protein (K670N, M671L) and from their nontransgenic littermates. Cortical and hippocampal tissue was microdissected at the onset of cognitive impairment, but before deposition of amyloid plaques. Crude synaptosomal fractions were prepared by differential centrifugation, proteins were separated by 2\u2010D DIGE and identified by MS\/MS. Significant alterations were detected in mitochondrial heat shock protein 70 pointing to a mitochondrial stress response. Subsequently, synaptosomal <jats:italic>versu<\/jats:italic>s nonsynaptic mitochondria were purified from Tg2576 mice brains by density gradient centrifugation. Mitochondrial proteins were separated by IEF or Blue\u2010native gel electrophoresis in the first dimension and SDS\u2010PAGE in the second dimension. Numerous changes in the protein subunit composition of the respiratory chain complexes I and III were identified. Levels of corresponding mRNAs remain unchanged as shown by Affymetrix oligonucleotide array analysis. Functional examination revealed impaired state 3 respiration and uncoupled respiration in brain mitochondria from young Tg2576 mice. By immunoblotting, amyloid\u2010beta oligomers were detected in synaptosomal fractions from Tg2576 mice and reduced glucose metabolism was observed in Tg2576 mice brains by [<jats:sup>14<\/jats:sup>C]\u20102\u2010deoxyglucose infusion. Taken together, we demonstrate alterations in the mitochondrial proteome and function that occur in Tg2576 mice brains before amyloid plaque deposition suggesting that mitochondria are early targets of amyloid\u2010beta aggregates.<\/jats:p>","DOI":"10.1002\/pmic.200600728","type":"journal-article","created":{"date-parts":[[2007,2,19]],"date-time":"2007-02-19T04:47:26Z","timestamp":1171860446000},"page":"605-616","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":124,"title":["Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition"],"prefix":"10.1002","volume":"7","author":[{"given":"Frank","family":"Gillardon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Rist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"Kussmaul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Danzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Kraut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Hengerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,2,19]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1067"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2005.00124.x"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1074069"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02621"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04533"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-02-00372.2001"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/6374"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-13-04691.2001"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/1615-9861(200103)1:3<377::AID-PROT377>3.0.CO;2-6"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5284.99"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.96.5.1374"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1385-299X(96)00011-6"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(86)91464-2"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69062564.x"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.4319\/lo.1995.40.6.1159"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(01)00307-3"},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500356200"},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001475"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/1615-9861(200208)2:8<969::AID-PROT969>3.0.CO;2-3"},{"key":"e_1_2_1_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.04.062"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079469"},{"key":"e_1_2_1_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01511"},{"key":"e_1_2_1_24_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-17-07380.2002"},{"key":"e_1_2_1_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206887"},{"key":"e_1_2_1_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1977.tb10649.x"},{"key":"e_1_2_1_27_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1091\/mbc.2.2.165","volume":"2","author":"Mizzen L. 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