Isoflurane has no effect on cognitive or behavioral performance in a mouse model of early-stage Alzheimer's disease.

Background: Patients with Alzheimer's disease show a sex-dependent decline of cognitive and behavioral performance. It is controversially discussed whether general anesthesia itself can aggravate or even cause this neurocognitive decline. Therefore, we investigated the effect of general anesthesia on neurocognitive and behavioral function and amyloidopathy in a mouse model of early-stage Alzheimer's disease with respect to sex. Methods: After governmental approval 10 months old Tg2576 mice and wild type (total 85 mice) either underwent general anesthesia with 1.0 minimal alveolar concentration of isoflurane for 2 h or were not exposed to isoflurane (controls). Following cognitive and behavioral testing using the modified hole board test (mHBT), brains were investigated regarding amyloidopathy, inflammation, and apoptosis. Data were analyzed using repeated measure analysis of variance (ANOVA) and univariate analysis of variance (UNIANOVA). Results: Tg2576 mice showed a decline in memory function (p < 0.001), less anxiety (p = 0.022 and p = 0.024), increased locomotor activity (p = 0.025), and impaired fine motor skills (p < 0.001). Amyloid precursor protein (p < 0.001), soluble amyloid-beta (p < 0.001) and insoluble amyloid deposits (p < 0.001) were increased in Tg2576 animals. Neither sex nor exposure to isoflurane had an effect on cognitive or behavioral testing or expression of amyloid-related biomarkers. Discussion and conclusion: We found that 10 months old Tg2576 showed typical signs of early-stage Alzheimer's disease and corresponding histopathological alterations. Relevant sex-specific differences or an effect of isoflurane anesthesia could not be detected at this early stage of the disease.

Influence of sex and hormonal status on initial impact and neurocognitive outcome after subarachnoid haemorrhage in rats.

The aim of this study was to detect differences in functional outcome after experimental subarachnoid haemorrhage (SAH) in rodents with different hormonal status. For this purpose, the endovascular perforation model was applied to four groups of Sprague-Dawley-Rats: male intact, male neutered, female intact and female neutered animals. Initial impact was measured by ICP, CPP and cerebral blood flow in the first hour after SAH. From day 4-14, the modified hole board test was applied to assess functional and neuro-cognitive outcome. Histological outcome was examined in the motor cortex and hippocampus of each hemisphere. Mortality was highest in the female intact group albeit not statistically significant. Physiologic parameters did not differ significantly between groups either. In the modified hole board test, male intact animals showed a greater impairment of declarative memory than the female intact and neutered groups. However, male intact animals showed greater avoidance behaviour and male animals revealed higher anxiety levels independent of hormonal status. No differences in histological damage of hippocampus and motor cortex between groups could be shown. We therefore speculate that the marginal deficits in cognitive performance that are shown by the male intact group in the modified hole board test are mostly caused by higher anxiety levels and cannot be interpreted as pure cognitive impairment.

Cognitive decline in Tg2576 mice shows sex-specific differences and correlates with cerebral amyloid-beta.

Patients suffering from Alzheimer's disease show a sex-dependent decline of cognitive function. The aim of this investigation was to show these differences in an animal model for Alzheimer's disease and to determine whether this effect is correlated to amyloid-beta-induced pathophysiological changes. Therefore, we assessed cognitive performance with the modified hole-board test in female and male Tg2576 and wild type mice at the age of 6, 8, 10, 12, 14, and 16 months and correlated these findings to the total amount of soluble amyloid-beta and insoluble amyloid deposits in the brain. Tg2576 mice perform worse than wild types. Female Tg2576 mice develop an accentuated cognitive impairment (wrong choice total) beginning at the age of 12 months compared to their male littermates. Alterations in the mice's behaviour do not show interference with these deficits. Cognitive impairment is correlated to the amount of soluble amyloid-beta and insoluble amyloid deposits in the brain in a sex-dependent manner.

Intracerebroventricular injection of beta-amyloid in mice is associated with long-term cognitive impairment in the modified hole-board test.

BACKGROUND: The intracerebroventricular injection of beta-amyloid (Aß) in mice allows the investigation of acute effects on cognitive function and cellular pathology. The aim of this investigation was to further characterize the time course of Aß-induced cognitive and behavioural changes and to detect potential molecular mechanisms. METHODS: Cannulas were implanted in the lateral cerebral ventricle. 14days after surgery the mice were injected with Aß1-42 or phosphate buffered saline (PBS). Starting 2, 4 or 8 (PBS only 4) days after injection we evaluated cognitive and behavioural performance using the modified hole board test (mHBT). We determined tumour-necrosis factor alpha (TNF alpha) and caspase 3 by western blotting, on days 10, 12 and 16. Data were analysed using general linear modelling, Kruskall-Wallis and Mann-Whitney-U test. RESULTS: Aß induced a decline in cognitive performance represented as an increased total number of wrong choices during the testing period from day 2-15 (p<0.05). Behavioural parameters were comparable between mice treated with Aß and PBS. There was no difference regarding TNF alpha levels between the groups. Compared to day 16 Caspase 3 levels were increased on day 10 (p=0.004). CONCLUSIONS: Application of Aß in the lateral ventricle of mice is associated with cognitive impairment of declarative memory in the mHBT. There is no interference caused by altered behaviour. Therefore, it represents a valid model for acute Aß-mediated neurotoxic effects. Although the exact mechanisms remain unclear, changes in levels of Caspase 3 suggest apoptosis as an important factor for the development of cognitive dysfunction.