Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats.

Non-alcoholic fatty liver disease (NAFLD) is a disorder observed in children and adults characterized by an accumulation of liver fat (>5% wet weight) in the absence of excessive alcohol intake. NAFLD affects 10 to 30% of the American population and is the most common cause of liver disease in the United States. NAFLD leads to serious disturbances in cardiovascular and hormonal function; however, possible effects on brain function have been overlooked. The aims of the present study were to test whether diet-induced NAFLD impairs hippocampal-dependent memory and to determine whether any observed deficits are associated with changes in hippocampal insulin signaling or concentrations of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). Post-weanling male Sprague-Dawley rats were fed a high fructose (60% of calories) or control diet for 12 weeks and then trained and tested in a spatial water maze. NAFLD was confirmed with postmortem measures of liver mass and liver lipid concentrations. NAFLD did not affect acquisition of the spatial water maze, but did impair retention tested 48 h later. Specifically, both groups demonstrated similar decreases in latency to swim to the escape platform over training trials, but on the memory test NAFLD rats took longer to reach the platform and made fewer visits to the platform location than control diet rats. There were no differences between the groups in terms of insulin-stimulated phosphorylation of insulin receptor ß subunit (IR-ß) and protein kinase B (PKB/AKT) in hippocampal slices or hippocampal BDNF or IGF-1 concentrations. Thus, these data indicate that NAFLD impairs hippocampal-dependent memory function and that the deficit does not appear attributable to alterations in hippocampal insulin signaling or hippocampal BDNF or IGF-1 concentrations.

A high fructose diet impairs spatial memory in male rats.

Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0% fructose) or high fructose diet (60% of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides.

Endogenous insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death.

Curiosity surrounding the physiological relevance of neural insulin signaling has gradually developed since the discovery that nervous tissue contains both the hormone and its receptor. Similar to other receptor tyrosine kinases, ligand interaction with the insulin receptor (IR) activates a variety of intracellular signaling pathways, particularly those relevant to cellular survival. Consequently, one explanation for the presence of the insulin pathway in the brain may involve participation in the response to neuronal injury. To investigate this possibility, the present study began by examining the effect of oxygen-glucose deprivation (OGD), a well-characterized in vitro model of ischemia, on ligand-binding, surface expression, and function of the IR in cultured rat neurons that were prepared under serum-free conditions. Reduced insulin-binding was observed following OGD, although surface expression of the receptor was not altered. However, OGD did significantly decrease the ability of insulin to stimulate phosphorylation of the transmembrane IR beta-subunit, without affecting protein expression of this subunit. Subsequent experiments focused on the manner in which pharmacologically manipulating IR function affected neuronal viability after OGD. Application of the IR sensitizer metformin moderately improved neuronal viability, while the specific IR tyrosine kinase inhibitor tyrphostin A47 was able to dramatically decrease viability; both compounds acted without affecting IR surface expression. Our study suggests that not only does the IR appear to play an important role in neuronal survival, but also that neurons may actively maintain IRs on the cell surface to compensate for the OGD-induced decrease in the ability of insulin to phosphorylate its receptor.

Chloroquine administration in mice increases beta-amyloid immunoreactivity and attenuates kainate-induced blood-brain barrier dysfunction.

The anti-malarial drug chloroquine (CHL) has been reported to cause the accumulation of beta-amyloid peptide containing fragments (fA beta) of the amyloid precursor protein within lysosomes in vitro. However, the significance of this finding with regards to the development of Alzheimer's disease (AD) pathology in vivo is not known. Hence, we investigated the effects of chronic CHL administration in the mouse. Systemically administered CHL caused an astrocytic response and an increase in intracellular A beta immunoreactivity throughout the brain, but no plaque-like pathology. Pharmacological challenge with the excitotoxin kainic acid (KA) revealed a mild proconvulsant effect of CHL pretreatment (P < 0.06). Interestingly, CHL protected the blood-brain barrier from characteristic KA-induced dysfunction. Given the hypothesized involvement of both excitotoxic processes and the vascular system in AD, the observed interactions may assist in elucidating the pathogenesis of AD.