Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP.

Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging.

Results from clinical studies provide evidence that cognitive changes relatively late in life may be traced to antecedent conditions including diabetes, obesity, a sedentary lifestyle, and an atherogenic diet. As such, several traits of Type 2 diabetes (T2DM) could be considered pathogenic factors of aging, contributing to age-dependent cognitive decline and our susceptibility to Alzheimer's disease. It appears that both the duration of metabolic condition and the age of the individual, together can contribute to the potential impact on peripheral as well as brain health. Because of robust evidence that in animal models of aging, Ca(2+) dysregulation alters neuronal health, synaptic plasticity, and learning and memory processes, we tested the hypothesis that peripheral metabolic dysregulation could exacerbate Ca(2+) dysfunction in hippocampal CA1 neurons. Using intracellular/ extracellular electrophysiological and Ca(2+) imaging techniques, we show that Ca(2+)levels at rest or during synaptic stimulation, the Ca(2+)-dependent afterhyperpolarization, baseline field potentials, and short-term synaptic plasticity were not significantly altered in young-adult male Zucker diabetic fatty rats compare to their lean counterparts. Our observations suggest that early phases of T2DM characterized by high levels of glucose and insulin may be too transient to alter hippocampal CA1 physiology in this animal model of diabetes. These results are supported by clinical data showing that longer T2DM duration can have greater negative impact on cognitive functions. This article is part of a Special Issue entitled SI: Brain and Memory.

Hippocampal calcium dysregulation at the nexus of diabetes and brain aging.

Recently it has become clear that conditions of insulin resistance/metabolic syndrome, obesity and diabetes, are linked with moderate cognitive impairment in normal aging and elevated risk of Alzheimer's disease. It appears that a common feature of these conditions is impaired insulin signaling, affecting the brain as well as peripheral target tissues. A number of studies have documented that insulin directly affects brain processes and that reduced insulin signaling results in impaired learning and memory. Several studies have also shown that diabetes induces Ca(2+) dysregulation in neurons. Because brain aging is associated with substantial Ca(2+) dyshomeostasis, it has been proposed that impaired insulin signaling exacerbates or accelerates aging-related Ca(2+) dyshomeostasis. However, there have been few studies examining insulin interactions with Ca(2+) regulation in aging animals. We have been testing predictions of the Ca(2+) dysregulation/diabetes/brain aging hypothesis and have found that insulin and insulin-sensitizers (thiazolidinediones) target several hippocampal Ca(2+)-related processes affected by aging. The drugs appear able to reduce the age-dependent increase in Ca(2+) transients and the Ca(2+) -sensitive afterhyperpolarization. Thus, while additional testing is needed, the results to date are consistent with the view that strategies that enhance insulin signaling can counteract the effect of aging on Ca(2+) dysregulation.

Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats.

The prevalence of obesity and type 2 diabetes increases with age. Despite this, few studies have examined these conditions simultaneously in aged animals, and fewer studies have measured the impact of these conditions on brain function. Using an established animal model of brain aging (F344 rats), we investigated whether a high-fat diet (HFD) exacerbates cognitive decline and the hippocampal calcium-dependent afterhyperpolarization (a marker of age-dependent calcium dysregulation). Young and mid-aged animals were maintained on control or HFD for 4.5 months, and peripheral metabolic variables, cognitive function, and electrophysiological responses to insulin in the hippocampus were measured. HFD increased lipid accumulation in the periphery, although overt diabetes did not develop, nor were spatial learning and memory altered. Hippocampal adiponectin levels were reduced in aging animals but were unaffected by HFD. For the first time, however, we show that the AHP is sensitive to insulin, and that this sensitivity is reduced by HFD. Interestingly, although peripheral glucose regulation was relatively insensitive to HFD, the brain appeared to show greater sensitivity to HFD in F344 rats.