аЯрЁБс>ўџ 68ўџџџ5џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅСo@№Пј%bjbj p p 4(ooB џџџџџџˆРРРРРРРдœœœœ4а д ьшшшшшшшшX Z Z Z Z Z Z $ RS >~ QРКшшКК~ РРшшЯ КŽРшРшX КX (ИРРИшм РщЋJІЦœH4ИX х 0 И‘| ‘ИддРРРР‘РИ ш„l^ЪLЄшшш~ ~ ддЄx$† ддxBRAIN INSULIN RECEPTOR SIGNALING CASCADE IN EXPERIMENTAL RAT MODEL RELATED TO THE HUMAN SPORADIC ALZHEIMER'S DISEASE `alkovi-Petriai M1, Grќnblatt E2, Hoyer S3, Riederer P2 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 Aim. Due to the slow, often imperceptible onset, and nature of the sporadic Alzheimer’s disease (sAD), initial pathophysiological changes and their further course in the human brain are unknown, making the search for an appropriate experimental model even more difficult. Decreased brain glucose/energy metabolism and cognitive deficits similar to those found in sAD, were reported in streptozotocin (STZ)-intracerebroventricularly (icv) treated rats, suggesting them as a probable experimental model of this disease. Study was aimed to explore the elements of brain insulin receptor (IR) signaling cascade and time-course of their changes in STZ-icv treated rats. Methods. Cognitive deficits (Morris Water Maze Swimming Test), neurochemical changes of IR signalling cascade elements (Western blot), gene expression changes of insulin-like growth factor 1 (IGF-1) receptor (quantitative-RT-PCR) and structural changes in beta amyloid aggregates (Congo red staining) in the brain of STZ-icv (1 mg/kg) rats, were measured d"three months following the STZ-icv treatment. Results. Hippocampal protein kinase B/Akt levels were mildly but insignificantly increased after one month, and mildly but significantly decreased (-9%) three months after STZ treatment. In line with that, the relative phosphorylated/non-phosphorylated glycogen synthase kinase-3 Б/В, pGSK-3Б/В /GSK-3Б/В ratio in hippocampus was found significantly increased (+50%) after one, and decreased (-9%) after three months. Mild increase in hippocampal total tau expression was found one month after STZ-icv treatment. Diffuse congophilic, beta amyloid-like aggregates were found in the meningeal capillaries three months after STZ-icv treatment. mRNA expression of IGF-1 receptor which shares signaling cascade pathway with IR and could compensate IR dysfunction, has been found decreased in the brain of STZ-icv treated rats. Neurochemical and structural changes in STZ-icv treated rats were accompanied by cognitive deficits that wereBRXrЂТшъью   . 0 4 B D \ ^ b d іьтітіеЫОЏ‰xjXjx‰x‰x@.hЯ*йhЧh_5CJH*OJQJ^JaJmH sH #hї9Phї9PCJH*OJQJ^JaJhї9PCJOJQJ^JaJ hЯ*йhЧh_CJOJQJ^JaJ&hЯ*йhЧh_5CJH*OJQJ^JaJ#hЯ*йhЧh_>*CJOJQJ^JaJhЯ*й>*CJOJQJ^JaJhЧh_hЯ*йOJQJ^JhЧh_OJQJ^JhЧh_hЧh_OJQJ^JhiЅOJQJ^JhŒгOJQJ^JhЯ*йOJQJ^Jъь` b W њ z { `u$˜%ј%їїђђђђђђээшээgdж94gdЧh_gdЧh_$a$gdЧh_ ј%ўd W X Ю ч њ ћ A f z {  €   — Є Ѕ Џ г к р  $ * < ‹ ыгыТыгыТыОЎŸ„uu„ui]iNhж94hgyCJOJQJ^Jhм0OCJOJQJ^Jh КCJOJQJ^Jhж94hbA‚CJOJQJ^Jhї9PCJOJQJ^Jhж94hNCJOJQJ^Jhж94hЧh_CJOJQJ^Jhж94hЧh_5CJOJQJ^JhЧh_ hЯ*йhЧh_CJOJQJ^JaJ.hЯ*йhЧh_5CJH*OJQJ^JaJmH sH (hЯ*йhЧh_CJOJQJ^JaJmH sH ‹  Й ќ §   = o  ‚ ‹ ‘ ” м ѓ Paiz˜™›љўAL[abcvётёгФИФёЉёИёЉИЉёФ~Ф~Ф~ФЉ~Ф~Фr~rФfФhqeCJOJQJ^Jh>M\CJOJQJ^Jhж94hп!CJOJQJ^Jhж94hЧh_5CJOJQJ^Jho{CJOJQJ^Jhж94h2іCJOJQJ^Jhм0OCJOJQJ^Jhж94hЧh_CJOJQJ^Jhж94hgyCJOJQJ^Jhж94hbA‚CJOJQJ^Jhж94hF;CJOJQJ^J$HZ^`prœтф4LNTќ0XlІЎjётгтФДЄ•‰г}‰•qeY•q•e•eJ•e•hж94hм0OCJOJQJ^JhqeCJOJQJ^Jhм0OCJOJQJ^JhѕEtCJOJQJ^JhxxCJOJQJ^JhmhCJOJQJ^Jhж94h€U!CJOJQJ^Jhж94hп!5CJOJQJ^Jhж94hЧh_5CJOJQJ^Jhж94hп!CJOJQJ^Jhж94hxxCJOJQJ^Jhж94hЧh_CJOJQJ^Jhж94hqeCJOJQJ^JjЌ&/2XbЂБУрё%'fgИЩг$.$l$s$t$u$€$$’$“$Ъ$ц$%3%єхжхєЪхОхОхОхЏєх хžОх papaUaєhм0OCJOJQJ^Jhж94hж94CJOJQJ^Jhж94hЧh_CJOJQJ^Jhж94hЧh_5CJOJQJ^Jhж94h‹VЇCJOJQJ^JUhж94hШБCJOJQJ^Jhж94hy-ЉCJOJQJ^JhmhCJOJQJ^Jho{CJOJQJ^Jhж94hxxCJOJQJ^Jhж94h€U!CJOJQJ^Jh!KCJOJQJ^J more pronounced with a longer duration of post-treatment period (-46% after three months vs. -33% after one month) Conclusion. STZ-icv rat model shares similarities with human sAD at the behavioural, structural and neurochemical level, and suggests that brain IR signaling alterations, observed in humans post-mortem mostly in the late stage of disease, may in fact be an early trigger in sAD generation. Acknowledgement. Supported by the Croatian Ministry of Science, Sports and Education, and DAAD. 3%E%b%c%g%o%|%Š%•%–%—%˜%Ј%Е%Й%и%ї%ј%єшмЭмЭшмЭОВЂ–Š–~Эhї9PCJOJQJ^Jh}Y”CJOJQJ^Jhж94CJOJQJ^Jhї9Phж945CJOJQJ^JhЧh_CJOJQJ^Jhж94hЧh_CJOJQJ^Jhж94hж94CJOJQJ^JhqeCJOJQJ^Jh!KCJOJQJ^Jhz#CJOJQJ^J21h:pп!А‚. 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