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Review
, 12 (3), 764-76

Food for Thought: The Role of Appetitive Peptides in Age-Related Cognitive Decline

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Review

Food for Thought: The Role of Appetitive Peptides in Age-Related Cognitive Decline

Jim R Fadel et al. Ageing Res Rev.

Abstract

Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimer's disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.

Keywords: Alzheimer's disease; Dementia; Hippocampus; Insulin; Leptin; Orexin.

Figures

Figure 1
Figure 1
The peptides insulin, leptin and orexin work in an integrative fashion to facilitate hippocampal synaptic plasticity. Insulin released from pancreatic β cells and leptin released from adipocytes have well defined metabolic activities in the hypothalamus that include regulation of orexin neuronal populations in the lateral hypothalamus, perifornical area and dorsomedial hypothalamus (blue arrows). Projection sites of these orexin populations include the basal forebrain, where orexin modulates cholinergic, GABAergic and glutamatergic components of septohippocampal neurotransmission (blue arrows). As such, these orexin-driven basal forebrain projections have a significant impact on hippocampal neurochemistry. Beyond these indirect effects, insulin and leptin can directly modulate hippocampal synaptic plasticity (red arrows), including facilitation of synaptic transmission (i.e. LTP), increases in neurogenesis and cell proliferation and promotion of synaptogenesis and dendritic remodeling (morphology). This facilitation of hippocampal synaptic plasticity ultimately leads to the enhancement of cognitive/behavioral function. See text for details.
Figure 2
Figure 2
Effect of Exendin-4 (EX4) on memory retention in the Barnes maze for STZ-diabetic mice. Mice were trained to learn the location of the box for 5 consecutive days in the Barnes maze, left untested for 3 day and then placed back on the Barnes maze where the box was removed but the cue was present. Panel A: Data represent the time to find the hole where the box was originally. Panel B: Percent of errors spent in the quadrant where the box was originally located. Data from control mice in white bars, Ex-4-treated control mice in grey bars, from untreated diabetic mice in black bars and from Ex-4-treated diabetic mice in hatched bars are mean+SEM, n=5–6/group. *p<0.05 vs diabetic+Ex-4 by one-way ANOVA followed by Bonferroni’s post-hoc test.

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