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The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid\u2010\u03b2 peptide (A\u03b2). By using double human mutant APP\/PS\u20101 knock\u2010in mice as the AD model, the present work demonstrates that the APP\/PS\u20101 double mutation results in elevated protein oxidation (as indexed by protein carbonyls), protein nitration (as indexed by 3\u2010nitrotyrosine), as well as lipid peroxidation (as indexed by protein\u2010bound 4\u2010hydroxy\u20102\u2010nonenal) in brains of mice aged 9 months and 12 months. APP\/PS\u20101 mice also exhibited lower levels of brain glutathione peroxidase (GPx) in both age groups studied, whereas glutathione reductase (GR) levels in brain were unaffected by the mutation. The activities of both of these antioxidant enzymes were significantly decreased in APP\/PS\u20101 mouse brains, whereas the activity of glucose\u20106\u2010phosphate dehydrogenase (G6PDH) was increased relative to controls in both age groups. Levels of peptidyl prolyl isomerase 1 (Pin1) were significantly decreased in APP\/PS\u20101 mouse brain aged 9 and 12 months. Administration of N\u2010acetyl\u2010L\u2010cysteine (NAC), a glutathione precursor, to APP\/PS\u20101 mice via drinking water suppressed increased protein oxidation and nitration and also significantly augmented levels and activity of GPx in brain from both age groups. Oral administration of NAC also increased the diminished activity of GR and protected against lipid peroxidation in brains of 9\u2010month\u2010old APP\/PS\u20101 mice only. Pin1 levels, GR levels, and G6PDH activity in brain were unaffected by oral administration of NAC in both age groups. These results are discussed with reference to the therapeutic potential of this brain\u2010accessible glutathione precursor in the treatment of MCI and AD. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22422","type":"journal-article","created":{"date-parts":[[2010,6,2]],"date-time":"2010-06-02T08:07:28Z","timestamp":1275466048000},"page":"2618-2629","source":"Crossref","is-referenced-by-count":79,"title":["Potential in vivo amelioration by N\u2010acetyl\u2010L\u2010cysteine of oxidative stress in brain in human double mutant APP\/PS\u20101 knock\u2010in mice: Toward therapeutic modulation of mild cognitive impairment"],"prefix":"10.1002","volume":"88","author":[{"given":"Quanzhen","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Aluise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gururaj","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rukhsana","family":"Sultana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daret K.","family":"St. Clair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Markesbery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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