аЯрЁБс>ўџ 24ўџџџ1џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅСo@№П$bjbj p p 4 oo’ џџџџџџˆ|||||||˜˜˜˜Д 1 ЖЬЬЬЬЬЬЬЬ€ ‚ ‚ ‚ ‚ ‚ ‚ $ч R9 ўІ E|žЬЬžžІ ||ЬЬы $ $ $ ž2|Ь|Ь€ $ ž€ $ ($ L ||L ЬР Pы{іаЦ˜а@L €  01 L 7 7L ||||7|L 4Ь„P^$ ЎLњЄЬЬЬІ І ФTD TBRAIN INSULIN SYSTEM AND SPORADIC ALZHEIMER'S DISEASE: EXPERIMENTAL APPROACH `alkovi-Petriai M1, Osmanovi J1, Hoyer S2, Riederer P3 1Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10 000 Zagreb, Croatia, melitas@mef.hr 2Department of Clinical Neurochemistry, University Department of Psychiatry and Psychotherapy, University of Wќrzburg, Fuechsleinstr. 15, 97080 Wќrzburg, Germany 3Department of Pathology, University Clinic, University of Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany Decreased brain glucose/energy metabolism and cognitive deficits similar to those found in sporadic Alzheimer’s disease (sAD), were reported in streptozotocin (STZ)-intracerebroventricularly (icv) treated rats, suggesting them as a probable experimental model of this disease. Initial pathophysiological changes and their course in the human brain are not completely understood. Alterations of brain insulin receptor (IR) signaling have been found in human sAD. Since STZ is selectively toxic to insulin producing/secreting cells, elements of brain IR signaling cascade, protein kinase B/Akt (PKB/Akt) and glycogen synthase kinase-3 (GSK-3) and time-course of their changes in STZ-icv treated rats were investigated. Cognitive deficits (Morris Water Maze Swimming Test), brain neurochemical changes of IR signalling elements (Western blot), and structural beta amyloid-related changes (Congo red staining) were measured 1 and 3 months following the STZ-icv (1 mg/kg) treatment. Mild decrease in hippocampal PKB/Akt was 3 months after the STZ-icv treatment in hippocampus, but not in frontal cortex. Relative pGSK-3/GSK-3 protein ratio was found increased (+50%) after 1, but decreased (-9%) after 3 months in hippocampus, and decrease after 1 and 3 months in frontal cortex of STZ-icv rats suggesting increment in non-phosphorylated, active form of GSK-3. In line with possible GSK-3 В subunit hyperactivity, total tau protein expression was found significantly increased after 1 month, while both total and phospho tau protein expression were intensively increased after 3 months. In addition, diffuse congophilic, beta amyloid-like aggregates were found in the meningeal capillaries three months after STZ-icv treatment. Cognitive deficits in learning and memory in STZ-icv rats were more pronounced in a longer post-treatment period. Based on the experimental model of sAD, brain IR signaling alterations may be an important factor in sAD generation, preceding Dj˜šœžТФШорфђє    іщпіщаОЊœŽzŽiXiXi@.hЯ*йhж]Ј5CJH*OJQJ^JaJmH sH  hж]Ј5CJH*OJQJ^JaJ hЯ*йhж]ЈCJOJQJ^JaJ&hЯ*йhЋ  5CJH*OJQJ^JaJhЋ  CJOJQJ^JaJhж]ЈCJOJQJ^JaJ&hЯ*йhж]Ј5CJH*OJQJ^JaJ#hЯ*йhж]Ј>*CJOJQJ^JaJhж]Ј>*CJOJQJ^JaJh/s2OJQJ^JhЧh_hж]ЈOJQJ^Jhж]ЈOJQJ^Jšœ  / в R S &„"$їїђђђђђђээшээцgdЋ  gdж]Јgdж]Ј$a$gdж]Ј$ў / 0 І П в г  > R S Ў Ь Я а і ї f h i  • › Ђ Ј Ю Я & g j z Œ г ж э ыгыТыгыТыОЏЃЏЃЏ—Џ—‹|p‹|‹ЃpЃpЃaЃaЃaЃaЃahж94hЋ  CJOJQJ^Jh9.CJOJQJ^Jhж94h/s2CJOJQJ^Jh/s2CJOJQJ^Jhж]ЈCJOJQJ^JhЋ  CJOJQJ^Jhж94hж]ЈCJOJQJ^Jhж]Ј hЯ*йhж]ЈCJOJQJ^JaJ.hЯ*йhж]Ј5CJH*OJQJ^JaJmH sH (hЯ*йhж]ЈCJOJQJ^JaJmH sH &V\Ђмъыђ&3JNЭ4xЮјq€Р"IXjmŠŽЊЧШЫ~‚ "$ёхёхйёйёхёхЭхЭСхСхСхСЭВЭВЭВхВхЭСЭёйёйАйёйёЅhж]ЈhЂ2mH sH Uhж94hЋ  CJOJQJ^Jh9.CJOJQJ^JhЋ  CJOJQJ^Jhж]ЈCJOJQJ^JhŠ3§CJOJQJ^Jhж94hж]ЈCJOJQJ^J+В-amyloid and tau protein related pathological hallmarks of sAD. Supported by the Croatian Ministry of Science, Sports and Education, and DAAD. 21h:pŠ3§А‚. 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