аЯрЁБс>ўџ 8:ўџџџ7џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅС%`№П $bjbjNрNр .(,Š,Šo џџџџџџЄ.вввв,ў .ƒЖЦШШШШШШ$9hЁ0ьQz z z ь=т т т z Цт z Цт т т   А‡+яшЩвˆ .т ЊS0ƒт бЖ бт бт Ш:Pрт 0Дф–ььЬ ƒz z z z ...Єв...в...џџџџ AD - AN INSULIN RESISTANT BRAIN STATE Salkovic-Petrisic Melita 1, Grќnblatt Edna 2, Osmanovic Jelena 1, Hoyer Siegfried 3 , Riederer Peter 2, 1Department of Pharmacology, University of Zagreb Medical School, Salata 11, 10 000 Zagreb, Croatia 2Department of Clinical Neurochemistry, Clinic for Psychiatry and Psychotherapy, University of Wќrzburg, Fќchsleinstrasse 15, 97080 Wќrzburg, Germany, 3Department of Pathology, University of Heidelberg, Im Neuenheimer Feld, 69120 Heidelberg, Germany Reports of impaired brain insulin receptor (IR) signaling being involved in cognitive decline, affecting also glucose utilization and energy metabolism, cell growth and differentiation, as well as metabolism of amyloid beta (AВ) and tau protein, have drawn an increasing attention in Alzheimer’s disease (AD) research. A growing body of evidence indicates indeed that sporadic type of AD (sAD) is associated with brain IR signaling abnormalities. Due to the slow, symptoms-free onset of sAD, their real role in sAD pathophysiology has remained unclear, leaving the follow up of IR dysfunction development to the animal AD models. Rats that have been intracerebroventricularly treated with streptozotocin (STZ-icv), a drug selectively toxic for insulin producing/secreting cells and IR, have been recognized recently as the experimental sAD model. Previous research of STZ-icv rat model reviled AD-like alterations; progressive memory deficits, decreased cholinergic transmission, reduced glucose/energy metabolism, oxidative stress, gliosis and neuronal loss in the brain. We investigated the time course and nature of brain insulin system dysfunction in this sAD model. Our results demonstrated alterations starting from the decreased insulin gene expression, followed by a decreased expression of IR mRNA and protein, found as early as 1 month following the induction of sAD-like condition and persisting up to 6 months afterwards. Downstream the IR-phosphatydilinositol-3 kinase signaling pathway decreased protein kinase Akt/PKB expression followed by a decreased phosphorylated/non-phosphorylated glycogen synthase kinase-3 (GSK-3Б/В) ratio, suggesting increased GSK-3 activity, was found not earlier than 3 months after the induction of sAD-like condition. This has eventually led to tau protein hyperphosphorylation and AВ aggregation found not earlier than 3 months after the di %&'@ARSfgyz{}ŒŽ‘нѓєѕE ] x ‰ ѕэѕэѕхкЯТЯЕЯТЯЈ•ЕЯТ‡|tgXMXMh?Nhш;tmH sH h?Nhш;tmH nH sH tH hш;tH*mH nH sH tH h?NmH sH h?Nh?NmH sH h?Nh?N0J5mH sH hш;tmH sH hш;thш;tmH sH hш;tH*mH nHsH tHhш;tH*mH nH sH tH hш;t0J5H*mH sH hш;th?NmH sH h&Z7hžV(mH sH hЂ2mH sH h&Z7mH sH h&Z7h&Z7mH sH &'єŒ я № ё $$$ $їїяяяяяъхррзЬ $dрa$gd?N Ц,gd9m'gd9m'gdIДgd}д$a$gd}д$a$gd}д  $ў‰ Œ  я № ё ђ  : > @ V b r Ќ В Д О Ъ Ю . 0 U \ j t … Џ Б Л П С Ш Ю л н G h z ” Ї јшйЭХСНЙЕЙЕЙНЙНЕЙБЙ­ЕЉЂБЂЕЂЕž—“ž“‹‡ž|t|hu,ЩB*phhIДhlщB*phhКh†IНhчlˆhНР hШ~/hШ~/h§P hШ~/hЌ jhГ|Gh(9hі9hЌ jh}дhСv\hИ˜hЌ jCJaJhјi6CJOJQJ^Jh?Nh?NmH nHsH tHh?Nh?NH*mH nHsH tHhш;tmH sH )Ї Ј Б Е Й я !(5>?@RgoƒЊУФЬецј "#6^eєщєсєсєсєжЫєжРЕЊŸ”Œ”ЊŒ”vŸvРv”Еv”ngc_h›0!hD Ч hg[xhg[xhі9B*phhg[xhcžB*phhg[xhlщB*phh›0!B*phhg[xhДЉB*phhg[xhТ{uB*phhg[xhu,ЩB*phhg[xhg[xB*phhg[xhCB*phhIДhIДB*phhIДhДЉB*phhu,ЩB*phhIДhlщB*phhIДhcžB*ph%ehx|‚ƒЛнрao‹Эю3N "l€ 2ŠŽІДМќ р ш !`!œ!Ј!Т!и!№!"$$$ќјќјќє№ь№є№є№є№сйсЮЦсЦсйсйсЮЦйЦЮОЦОЮЖДЖЌЖЌЖЁЖЁЖЁ–Д–‹h§PhИ˜CJaJh§PhТ{uCJaJhIpкhТ{uCJaJhžXCJaJUhИ˜CJaJh§PCJaJhIpкCJaJhIpкhIpкCJaJh›0!CJaJhIpкh#&CJaJhИ˜h#&h[Ah§PhD Ч4sease induction as the cerebral amyloid angiopathy followed by a primitive plaque-like formation 6 months after the STZ-icv treatment. Therefore, sAD could be considered as an insulin resistant brain state which precedes and eventually triggers AВ pathology. Supported byDAAD and MZOS. $$$$$$ $јэтэтзh§Ph?NmH sH h§Ph9m'CJaJh§Ph§PCJaJh9m'CJaJ,1hА‚. 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