аЯрЁБс>ўџ 9;ўџџџ8џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅСo@№ПФ'bjbj p p .*ooЏ џџџџџџˆЈЈЈЈЈЈЈМDDDD4xМƘ˜˜˜˜˜˜˜fhhhhhh$ЭRВŒEЈц ˜˜ц ц ŒЈЈ˜˜бКККц PЈ˜Ј˜fКц fК(КтЈЈт˜Œ №tAх[ЧD6Xтfч0тбŽ"бтММЈЈЈЈбЈт„˜ЈТКj œ р˜˜˜ŒŒММЄ`фА ММ`MODELLING SPORADIC ALZHEIMER’S DISEASE Salkovic-Petrisic Melita Grќnblatt Edna Osmanovic Jelena Hoyer Siegfried Riederer Peter University of Zagreb Medical School Department of Pharmacology and Croatian Brain Research Institute Salata 11 10 000 Zagreb, Croatia University of Wќrzburg Department of Clinical Neurochemistry, Clinic for Psychiatry and Psychotherapy Fќchsleinstrasse 15 97080 Wќrzburg, Germany University of Heidelberg Department of Pathology Im Neuenheimer Feld 69120 Heidelberg, Germany. Based on similarities in cognitive deficits and decreased brain glucose/energy metabolism and oxidative stress, streptozotocin-intracerebroventricularly (STZ-icv) treated rats were proposed as the experimental sporadic Alzheimer’s disease (sAD) model which is not related to gene manipulations. To further characterize this model we investigated the brain insulin system and influence of its dysfunction on tau protein and amyloid beta (AВ) peptide. Gene expression of insulin and insulin receptor (IR), alterations of IR-beta subunit, IR tyrosine kinase (TK) activity, expression of protein kinase B (Akt/PKB), glycogen synthase kinase 3 (GSK-3) and tau protein were measured by RT-PCR, ELISA, TK assay and Western blot in frontoparietal cortex (CTX) and hippocampus (HPC) of adult STZ-icv (1 mg/kg) treated rats. AВ aggregates were visualised by Congo red staining. Cognitive deficits were measured in Morris Water Maze Test. Data were analysed by Cruscal-Walles ANOVA and Mann-Whitney U test (P<0.05). Expression of insulin-1 (HPC) and -2 (CTX) and IR mRNA (CTX, HPC) was decreased. Phosphorylated IR-beta subunit content was increased (CTX) and TK activity increased (HPC). Akt/PKB and phosphorylated/non-phosphorylated GSK-3'?@CNO_`op€”ЃЄЬлрфяіьлЭПлЭлЭлЭлПЇ’}ePeP’>"hлiЈCJOJQJ^JaJmH sH )h3}y0J5CJOJQJ^JaJmH sH /hKh3}y0J5CJOJQJ^JaJmH sH (hˆHhѓ{CJOJQJ^JaJmH sH )hˆH0J5CJOJQJ^JaJmH sH /hKhˆH0J5CJOJQJ^JaJmH sH h3}yCJOJQJ^JaJhˆHCJOJQJ^JaJ hKh3}yCJOJQJ^JaJ&h3}y5B*CJOJQJ^JaJph'@O`p€Єхяі   n ‚ ˆ š › Д Ь р ц ћ § D F њњњњњњњњњњњњњњњњњњђђђђђђэээgd3}y$a$gd3}ygd3}yФ'§і        F O ˆ Š ™ š › ывМІ‘‘fМвІT?ы(-hˆHCJH*OJQJ^JaJmH nHsH tH(hKh3}yCJOJQJ^JaJmH sH "h3}yCJOJQJ^JaJmH sH 0hKhˆHCJOJQJ^JaJmH nH sH tH "hˆHCJOJQJ^JaJmH sH (hKhˆHCJOJQJ^JaJmH sH *hˆHCJOJQJ^JaJmH nH sH tH *h3}yCJOJQJ^JaJmH nH sH tH 0hKh3}yCJOJQJ^JaJmH nH sH tH (hKh3}yCJOJQJ^JaJmH sH › Г ц ћ ќ §  7 = T k Х Я э № ё ї F G W [ o p } чбИЌ ”ˆ”|”p”dXdXdXL”LXLphУCJOJQJ^JhaJуCJOJQJ^JhGCJOJQJ^JhСkRCJOJQJ^JhЂodCJOJQJ^JhG<’CJOJQJ^JhOCCJOJQJ^Jh3}yCJOJQJ^Jh=4HCJOJQJ^J0hKh3}yCJOJQJ^JaJmH nHsH tH*hˆHCJOJQJ^JaJmH nHsH tH0hKhˆHCJOJQJ^JaJmH nHsH tH} ~ ‘ > B D F z ‚ Є І Ј Ќ Ў В о ђ ј 2 R l Š І Ј К М а ќ 0@bh P†Œ˜КШіўєшєшмаФЕЉЉЉЉ‘ЕЉЕЉє…є…єЕ…ЕЉ…ЕyЕyЕ…y…y…Ф…h1sCJOJQJ^Jh€iСCJOJQJ^Jh3}yCJOJQJ^JhСkRCJOJQJ^Jh kОCJOJQJ^Jhvvтh3}yCJOJQJ^JhGCJOJQJ^JhE:LCJOJQJ^JhOCCJOJQJ^JhУCJOJQJ^JhBCJOJQJ^J,ўMNOPy”ž ЁЮжйоѕіљњ"""""4":"<"Ђ"Є"Њ"Ќ"Ў"Ж"И"К"М"т"ф"ц"К#$$$$,$єшмЭНЊНЊНЊНЊНЊНЊНЊНЊЈœЊœЊНЊНЊНЊНЊŒЊœЊŒЊŒЊНЊœuhн4ZCJOJQJ^Jhr4њhr4њmH sH hG<’CJOJQJ^JmH sH hr4њCJOJQJ^JU$hr4њhr4њCJOJQJ^JmH sH hr4њCJOJQJ^JmH sH hvvтhGCJOJQJ^Jh3}yCJOJQJ^Jhс<аCJOJQJ^JhV “CJOJQJ^J.F NO$$L'М'О'Р'Т'Ф'њњђњњъхуууgd3}y$a$gd3}y$a$gdr4њgd3}y Б/В ratio were decreased (HPC) GSK-3-related hyperphosphorylation of tau protein (HPC) and AВ aggregates in meningeal capillaries were found not earlier than 3 months after STZ-icv treatment. Cognitive deficits were found as early as 2 weeks after STZ-icv treatment. STZ-icv is a representative experimental sAD model which, in general, shares with human sAD also region- and time-dependent similarities in brain insulin system dysfunction. Such a modelling of sAD enabled the conclusion that instead of AВ, imbalance in IR signaling cascade phosphorylation/dephosphorylation and insulin resistant brain state could be the primary pathological event in sAD ethiopathogenesis. Supported by Croatian MZOS (108-1080003-0020) and DAAD. ,$~$ˆ$Ђ$А$В$Ю$к$%X%t%Є%в%к%Š&и&ъ&J'L'М'О'Р'Т'Ф'єшмшєаєФИєшЌє єаФ”jbZOh3}yhr4њmH sH hr4њmH sH hЂ2mH sH (h9?[h3}yCJOJQJ^JaJmH sH (hѓ{h3}yCJOJQJ^JaJmH sH h3}yCJOJQJ^Jh1sCJOJQJ^JhУCJOJQJ^Jh=4HCJOJQJ^Jhѓ{CJOJQJ^JhGCJOJQJ^JhG<’CJOJQJ^Jhн4ZCJOJQJ^JhЂodCJOJQJ^J,1hА‚. 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