Mulberry fruit extract alleviates the intracellular amyloid-ß oligomer-induced cognitive disturbance and oxidative stress in Alzheimer's disease model mice.

Intracellular amyloid-ß (Aß) oligomers are key therapeutic targets because they are strongly cytotoxic and play crucial roles in the cognitive function in Alzheimer's disease (AD). Anthocyanins, polyphenolic flavonoids with antioxidant and neuroprotective properties, are potential therapeutic candidates for AD. Here, we investigated the effects of anthocyanin-enriched extracts from fruits of mulberry (Morus alba Linn.) in Thailand against the neurotoxicity of Aß oligomers. Using the monitoring system for Aß aggregation, we showed that the extract induced the dissociation of Aß in cultured HEK293T cells. To investigate the effects on cognitive function, we orally administered the extract to Aß-GFP transgenic mice (Aß-GFP Tg), a mouse model that expresses Aß oligomers inside neurons, and performed the novel object recognition test and passive avoidance test. Aß-GFP Tg usually showed deficits in novel object recognition memory and reference memory compared with non-Tg, but administration of the extract improved both compared with vehicle-treated Aß-GFP Tg. Aß-GFP Tg exhibited lower superoxide dismutase (SOD) activity than non-Tg. However, after the administration of the extract, the SOD activity was restored. These results suggest that Thai mulberry fruit extract ameliorates cytotoxicity induced by the intracellular Aß oligomers and may be an effective therapeutic or preventive candidate for AD.

New Alzheimer's disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid ß oligomers.

Oligomers of intracellular amyloid ß protein (Aß) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer's disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of Aß oligomers only. We have now developed a novel AD model mouse, an Aß-GFP transgenic mouse (Aß-GFP Tg), that expresses the GFP-fused human Aß1-42 protein, which forms only Aß oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The Aß-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2-3-months-old animals. The Aß-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated Aß oligomer derived from postmortem AD patient brains and synthetic Aß oligomers. Thus, Aß-GFP Tg mouse is a new tool specialized to analyze the function of Aß oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.

Can rats control previously acquired spatial information? Evidence of "directed forgetting" phenomenon in delay-interposed radial maze behavior.

"Directed forgetting" is a method and a phenomenon used to investigate whether organisms can control memory with instructions to forget, and to remember. We examined directed forgetting phenomenon in rats, using a modified radial maze task. In the delay-interposed radial maze task, a 120-min delay followed four correct choices, during which rats were placed in either a white or black box, that signaled whether a second-half performance will be required (remember (R)-trial), or not (forget (F)-trial) after the delay. R- and F-trials were repeated 5 times each, followed by a "probe test," in which the second-half performance was conducted, although the F-cue was presented during the delay period. Rats made more errors in the probe test than in the R-trial. These results demonstrate the "directed forgetting" phenomenon in a radial maze task in rats, and suggest that rats can indeed control previously acquired spatial information, even situations with a long retention interval interposed. Although the mechanism by which presentation of the "forget-cue" influences rats' information processing remains unclear, several brain regions, including the medial prefrontal cortex and the hippocampal CA3 area, were shown to be more activated in the "remember"-cued trial than in the "forget"-cued trial, suggesting that these areas are potentially related to the "directed forgetting" phenomenon of spatial information demonstrated in the study.

Effects of intrahippocampal cannabinoid receptor agonist and antagonist on radial maze and T-maze delayed alternation performance in rats.

Brain cannabinoid receptors are abundantly distributed in the hippocampus, however their detailed role in learning and memory remains unclear. This study investigated the role of hippocampal cannabinoid receptors for performing two kinds of working memory tasks. In experiment 1, intrahippocampal infusion of cannabinoid receptor agonist WIN 55,212-2 (1-2 microg/side) dose-dependently disturbed radial maze performance in rats. In experiment 2, WIN 55,212-2 (2 microg/side) disturbed the performance of delayed alternation in a T-maze by increasing the errors and successive errors, and on the other hand, a cannabinoid receptor antagonist AM 281 (1 microg/side) did not have any significant effects. Disruptive effect of WIN 55,212-2 on the number of errors in delayed alternation was blocked by the pretreatment with intraperitoneal AM 281 (2 mg/kg). Results suggest that hippocampal cannabinoid receptors are involved in the performance of working memory tasks. A possible role of endogenous cannabinoid system in the hippocampus was discussed in terms of an inhibitory adjustment of behavior based on the outcome of animals' previous response.