Insulin-like growth factor-2 is a promising candidate for the treatment and prevention of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. Current AD treatments slow the rate of cognitive decline, but do not restore lost function. One reason for the low efficacy of current treatments is that they fail to target neurotrophic processes, which are thought to be essential for functional recovery. Bolstering neurotrophic processes may also be a viable strategy for preventative treatment, since structural losses are thought to underlie cognitive decline in AD. The challenge of identifying presymptomatic patients who might benefit from preventative treatment means that any such treatment must meet a high standard of safety and tolerability. The neurotrophic peptide insulin-like growth factor-2 (IGF2) is a promising candidate for both treating and preventing AD-induced cognitive decline. Brain IGF2 expression declines in AD patients. In rodent models of AD, exogenous IGF2 modulates multiple aspects of AD pathology, resulting in (1) improved cognitive function; (2) stimulation of neurogenesis and synaptogenesis; and, (3) neuroprotection against cholinergic dysfunction and beta amyloid-induced neurotoxicity. Preclinical evidence suggests that IGF2 is likely to be safe and tolerable at therapeutic doses. In the preventative treatment context, the intranasal route of administration is likely to be the preferred method for achieving the therapeutic effect without risking adverse side effects. For patients already experiencing AD dementia, routes of administration that deliver IGF2 directly access the CNS may be necessary. Finally, we discuss several strategies for improving the translational validity of animal models used to study the therapeutic potential of IGF2.

Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin.

Thyroid hormone's role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes.

Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often encountered in combination with metabolic disorders such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. TH's potential as a regulator of brain glucose metabolism is heightened by interactions with insulin signaling, but there have been relatively few studies on this topic or on the actions of TH in a mature brain. This review discusses evidence for mechanistic links between TH, insulin, cognitive function, and brain glucose metabolism, and reaches the conclusion that TH may modulate memory processes, likely at least in part by modulation of central insulin signaling and glucose metabolism.

Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes.

In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin-requiring diabetes (40 +/- 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means +/- SE, area under the curve over time (AUC/t) 144 +/- 43 vs. 50 +/- 11 ng.l(-1).min(-1); P < 0.05] and epinephrine [4.27 +/- 0.96 vs. 1.06 +/- 0.26 nmol.l(-1).min(-1); P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 +/- 22 vs. 85 +/- 22 ng.l(-1).min(-1); P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.

Effects of recurrent antecedent hypoglycaemia and chronic hyperglycaemia on brainstem extra-cellular glucose concentrations during acute hypoglycaemia in conscious diabetic BB rats.

AIMS/HYPOTHESIS: Our aim was to determine whether the divergent effects of chronic exposure to hyperglycaemia or hypoglycaemia on the glycaemic threshold for auditory brainstem dysfunction are reflected in the extra-cellular fluid (ECF) concentrations of glucose in the inferior colliculus during hypoglycaemia in the diabetic BB rat. METHODS: Microdialysis was used to measure inferior colliculus ECF glucose concentrations under basal and hyperinsulinaemic (20 mU/kg.min) hypoglycaemic conditions. RESULTS: ECF glucose is increased under basal (hyperglycaemic) conditions and decreases during hypoglycaemia in both recurrently hypoglycaemic and chronically hyperglycaemic diabetic BB rats (to 0.5+/-0.1 and 0.8+/-0.2 mmol/L respectively), with no significant differences between groups. In both groups the plasma to ECF glucose ratio doubled during hypoglycaemia. CONCLUSION/INTERPRETATION: Prior exposure to recurrent hypoglycaemia does not lead to increased ECF glucose concentrations in the inferior colliculus of diabetic BB rats. The resistance to impaired brainstem function seen in recurrently hypoglycaemic rats during hypoglycaemia cannot simply be attributed to increased blood-brain barrier glucose transport within this brain region.

Fluctuations in brain glucose concentration during behavioral testing: dissociations between brain areas and between brain and blood.

Traditional beliefs about two aspects of glucose regulation in the brain have been challenged by recent findings. First, the absolute level of glucose in the brain's extracellular fluid appears to be lower than previously thought. Second, the level of glucose in brain extracellular fluid is less stable than previously believed. In vivo brain microdialysis was used, according to the method of zero net flux, to determine the basal concentration of glucose in the extracellular fluid of the striatum in awake, freely moving rats for comparison with recent hippocampal measurements. In addition, extracellular glucose levels in both the hippocampus and the striatum were measured before, during, and after behavioral testing in a hippocampus-dependent spontaneous alternation task. In the striatum, the resting extracellular glucose level was 0.71 mM, approximately 70% of the concentration measured previously in the hippocampus. Consistent with past findings, the hippocampal extracellular glucose level decreased by up to 30 +/- 4% during testing; no decrease, and in fact a small increase (9 +/- 3%), was seen in the striatum. Blood glucose measurements obtained during the same testing procedure and following administration of systemic glucose at a dose known to enhance memory in this task revealed a dissociation in glucose level fluctuations between the blood and both striatal and hippocampal extracellular fluid. These findings suggest, first, that glucose is compartmentalized within the brain and, second, that one mechanism by which administration of glucose enhances memory performance is via provision of increased glucose supply from the blood specifically to those brain areas involved in mediating that performance.

Age-related differences in hippocampal extracellular fluid glucose concentration during behavioral testing and following systemic glucose administration.

Recent evidence indicates that the level of glucose in the brain's extracellular fluid (ECF) is not constant, as traditionally thought, but fluctuates. We determined the effect of aging on hippocampal ECF glucose before, during, and after spatial memory testing. Fischer-344 rats (24 months old) showed a greater decrease in ECF glucose than 3-month-old rats (48% vs 12%); the decrease seen in 24-month-old rats persisted for much longer following testing. These changes were associated with an age-related deficit in spontaneous alternation performance. Following systemic glucose administration, the decrease in ECF glucose was reversed in both aged and young rats, and performance in aged versus young rats following glucose administration did not differ. These findings suggest that increased susceptibility to depletion of ECF glucose in aged rats may contribute to age-related deficits in learning and memory and that administration of glucose may enhance memory by providing additional glucose to the brain at times of increased cognitive demand.

Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task.

Using in vivo microdialysis, we measured hippocampal extracellular glucose concentrations in rats while they performed spontaneous alternation tests of spatial working memory in one of two mazes. Extracellular glucose levels in the hippocampus decreased by 32% below baseline during the test period on the more complex maze, but by a maximum of 11% on the less complex maze. Comparable decreases were not observed in samples taken from rats tested on the more complex maze but with probes located near but outside of the hippocampus. Systemic glucose fully blocked any decrease in extracellular glucose and enhanced alternation on the more complex maze. These findings suggest that cognitive activity can deplete extracellular glucose in the hippocampus and that exogenous glucose administration reverses the depletion while enhancing task performance.

Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux: effects of microdialysis flow rate, strain, and age.

The concentration of glucose in the brain's extracellular fluid remains controversial, with recent estimates and measurements ranging from 0.35 to 3.3 mM. In the present experiments, we used the method of zeronet-flux microdialysis to determine glucose concentration in the hippocampal extracellular fluid of awake, freely moving rats. In addition, the point of zero-net-flux was measured across variations in flow rate to confirm that the results for glucose measurement were robust to such variations. In 3-month-old male Sprague-Dawley rats, the concentration of glucose in the hippocampal extracellular fluid was found to be 1.00 +/- 0.05 mM, which did not vary with changes in flow rate. Three-month-old and 24-month-old Fischer-344 rats both showed a significantly higher hippocampal extracellular fluid glucose concentration, at 1.24 +/- 0.07 and 1.21 +/- 0.04 mM, respectively; there was no significant difference between the two age groups. The present data demonstrate variation in extracellular brain glucose concentration between rat strains. When taken together with previous data showing a striatal extracellular glucose concentration on the order of 0.5 mM, the data also demonstrate variation in extracellular glucose between brain regions. Traditional models of brain glucose transport and distribution, in which extracellular concentration is assumed to be constant, may require revision.

Memory modulation across neural systems: intra-amygdala glucose reverses deficits caused by intraseptal morphine on a spatial task but not on an aversive task.

Based largely on dissociations of the effects of different lesions on learning and memory, memories for different attributes appear to be organized in independent neural systems. Results obtained with direct injections of drugs into one brain region at a time support a similar conclusion. The present experiments investigated the effects of simultaneous pharmacological manipulation of two neural systems, the amygdala and the septohippocampal system, to examine possible interactions of memory modulation across systems. Morphine injected into the medial septum impaired memory both for avoidance training and during spontaneous alternation. When glucose was concomitantly administered to the amygdala, glucose reversed the morphine-induced deficits in memory during alternation but not for avoidance training. These results suggest that the amygdala is involved in modulation of spatial memory processes and that direct injections of memory-modulating drugs into the amygdala do not always modulate memory for aversive events. These findings are contrary to predictions from the findings of lesion studies and of studies using direct injections of drugs into single brain areas. Thus, the independence of neural systems responsible for processing different classes of memory is less clear than implied by studies using lesions or injections of drugs into single brain areas.

Deficit in learning of a motor skill requiring strategy, but not of perceptuomotor recalibration, with aging.

We investigated the effect of aging on different aspects of motor skill learning using two computer-presented perceptuomotor tasks. The relationship between visual and proprioceptive feedback was transformed in the first task, which was open to the formation and use of strategies. This task was designed to lead to perceptuomotor adaptation that was then measured by performance on a very similar second task that was not open to the use of strategy task. Older participants showed impaired learning of the strategic task but not of the nonstrategic task. This is in line with the suggestion that the effect of aging on learning and memory may be to reduce working memory resources.