Naslov
Amyloid cascade hypothesis: is it true for sporadic Alzheimer’ s disease?

Autori
Šalković-Petrišić, Melita ; Grünblatt, Edna ; Osmanović, Jelena ; Hoyer, Siegfried ; Riederer, Peter

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Period Biol. Suppl 2 / Vitale, Branko - Zagreb : Hrvatsko prirodoslovno društvo, 2007, 44-44

Skup
5th Croatian Congress of Pharmacology and 2nd Congress of Croatian Physiological Society

Mjesto i datum
Period biol 2007 ; 109:suppl 2:44., 19.09.2007. - 22.09.2007

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
Sporadic Alzheimer's Disease; Streptozotocin Rat Model; Brain Insulin

Sažetak
Huge progress in understanding and treating of Alzheimer's disease (AD) has started whith the era of AD modeling. However, experimental model that recapitulates all aspects of Alzheimer's disease (AD) has not yet been produced although various transgenic mouse lines have been designed that offer relatively faithful reproductions of some of the main neuropathologicall features ; extracellular senile plaques composed of unsoluble amyloid beta (A&#946; ) fibrilles, and intraneuronal neurofibrillary tangles composed of hyperphosphorylated form of microtubule associated protein tau. Currently, the leading hypothesis assumes that pathological assemblies of A&#946; are the cause of all forms of AD, whereas other neuropathological changes are downstream consequences of pathological A&#946; accumulation. However, this hypothesis fits only to the familial, early onset type of AD caused by mutations in three particular A&#946; -related genes, while the great majority of AD patients have sporadic late-onset type of disease (sAD) with age and several susceptibility genes as risk factors. In line with the brain insulin dysfunction found post-mortem in sAD patients, streptozotocin-intracerebroventricularly treated rats (STZ-icv) have been recently proposed as an experimental model for sAD because STZ is a drug selectively toxic for insulin producing/secreting cells. Central, icv application of STZ is associated with progressive deficits in learning and memory, decrement in cholinergic transmission and decreased glucose and energy metabolism in the brain. To further characterize this model we investigated the brain insulin system and influence of its dysfunction on tau protein and amyloid beta (A&#946; ) peptide following STZ-icv administration. 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. A&#946; 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&#945; /&#946; ratio were decreased (HPC) GSK-3-related hyperphosphorylation of tau protein (HPC) and A&#946; 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. Results support STZ-icv rat as a representative experimental sAD model which suggests that instead of A&#946; , 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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