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: 5.29). 12/2011; 46(1):4-10. DOI: 10.1007/s12035-011-8229-6
Source: PubMed

ABSTRACT 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, Aug 14, 2015
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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.
    Learning & memory (Cold Spring Harbor, N.Y.) 10/2014; 21(10):556-63. DOI:10.1101/lm.029348.112 · 4.38 Impact Factor
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    • "A recent study has reported protective effects in aged APP/PS1 mice, demonstrating that liraglutide can reverse at least some of the symptoms of AD (McClean and Holscher, 2013). Insulin treatment in mouse models and in control subjects that aim to test the effect of insulin applied intranasally has also shown good effects (Strachan, 2005; Reger et al., 2008; Schioth et al., 2012). These clear effects motivated clinical trials in AD patients, testing nasal insulin application on key parameters of AD. "
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    ABSTRACT: Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves many underlying pathological processes. Recently, it has been demonstrated that AD also includes impairments of insulin signaling in the brain. Type 2 diabetes is a risk factor for AD, and AD and diabetes share a number of pathologies. The classical hallmarks of AD are senile plaques and neurofibrillary tangles, which consist of amyloid-β and hyperphosphorylated tau. Based on the two hallmarks, transgenic animal models of AD have been developed, which express mutant human genes of amyloid precursor protein, presenilin-1/2, and tau. It is likely that these mouse models are too limited in their pathology. In this work, we describe mouse models that model diabetes and show insulin signaling impairment as well as neurodegenerative pathologies that are similar to those seen in the brains of AD patients. The combination of traditional AD mouse models with induced insulin impairments in the brain may be a more complete model of AD. Interestingly, AD mouse models treated with drugs that have been developed to cure type 2 diabetes have shown impressive outcomes. Based on these findings, several ongoing clinical trials are testing long lasting insulin analogues or GLP-1 mimetics in patients with AD.
    Reviews in the neurosciences 12/2013; 24(6):607-615. DOI:10.1515/revneuro-2013-0034 · 3.31 Impact Factor
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    • "It is noteworthy that the use of intranasal administration of recombinant Hsp70 is not the first attempt to treat AD-like symptoms. Thus, intranasal administration of insulin was found effective to modulate verbal memory and plasma A␤ in memory-impaired older adults and in other model systems [48] [49]. Taken together, our findings not only establish exogenous Hsp70 as a potentially practical pharmacological agent for the treatment of various neurodegenerative diseases, but also reveal novel functions of mammalian Hsp70. "
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    ABSTRACT: Brain deterioration resulting from "protein folding" diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-β (Aβ) peptide and, in the case of 5XFAD mice, reduces Aβ plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed.
    Journal of Alzheimer's disease: JAD 08/2013; 38(2). DOI:10.3233/JAD-130779 · 4.15 Impact Factor
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