Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions

Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden.
Molecular Neurobiology (Impact Factor: 5.14). 12/2011; 46(1):4-10. DOI: 10.1007/s12035-011-8229-6
Source: PubMed


Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.

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Available from: Christian Benedict
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    • "Notably, both insulin and IGF1 peptides are being tested in clinical trials as treatments for Alzheimer's disease (AD) and autism, respectively (Schiöth et al. 2012; Freiherr et al. 2013; Khwaja et al. 2014). Previous work in our laboratory has shown that IGF2 expression is up-regulated following learning under the functional control of the transcription factor CCAAT enhancer binding protein b (C/EBPb), and that its functional role is necessary for inhibitory avoidance (IA) memory consolidation. "
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    ABSTRACT: Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.
    Full-text · Article · Oct 2014 · Learning & memory (Cold Spring Harbor, N.Y.)
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    • "By the intranasal method, insulin effectively bypasses the BBB and can be delivered into the brain. Clinical trials have demonstrated that intranasal insulin has some beneficial effects on cognition in patients with mild cognitive impairment and AD.93 GLP-1 analogs have been demonstrated to exert neuroprotective and aniapoptotic effects, reduce Aβ plaque accumulation, modulate long-term potentiation and synaptic plasticity, and promote the differentiation of neuronal progenitor cells. In animal models of behavior, treatment with GLP-1 receptor agonists has been demonstrated to improve measures of cognitive function, including learning and memory, as well as to reduce depressive behavior.94 "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction and dementia in the elderly. T2DM has been thought to be associated with vascular diseases, eventually leading to vascular dementia, but recent studies have established that T2DM is also associated with Alzheimer's disease (AD). With the increase in the number of elderly individuals with T2DM, the number of diabetic patients with cognitive dysfunction has been increasing. T2DM may accelerate AD-associated pathologies through insulin resistance. Vascular pathologies may also be associated with cognitive dysfunction and dementia in T2DM subjects. Several other mechanisms also seem to be involved in T2DM-related cognitive dysfunction. More investigations to clarify the association of T2DM with cognitive impairment are warranted. These investigations may help to increase our understanding of AD and open a new door to the development of therapeutics. Recent pharmaceutical advancement in T2DM treatment has resulted in the availability of a wide range of antidiabetics. Some evidence has suggested that antidiabetic therapies help to prevent cognitive dysfunction. At present, however, the optimal level of blood glucose control and the best combination of medications to achieve it in terms of cognitive preservation have not been established. More investigation is warranted. Cognitive dysfunction is an emerging new complication of T2DM that requires further study.
    Full-text · Article · Jun 2014 · Clinical Interventions in Aging
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    • "Evidence that insulin signaling mechanisms are important for neuronal survival [9,29] and studies demonstrating reduced expression of the insulin receptor in the brain of patients suffering from AD have generated increased interest in determining the role of impaired insulin actions associated with Alzheimer-like changes [5]. The fact that insulin receptors are widely expressed in the brain, combined with the observation that insulin crosses the blood-brain barrier by a saturable, receptor mediated transport mechanism, further highlights the observations that insulin likely plays a key role in memory and cognition [30,31]. Defective insulin signaling is associated with decreased cognitive ability and development of dementia. "
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    ABSTRACT: Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain.
    Full-text · Article · Dec 2013 · PLoS ONE
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