Article

Craft, S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr. Alzheimer Res. 4, 147-152

Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Current Alzheimer Research (Impact Factor: 3.8). 05/2007; 4(2):147-52. DOI: 10.2174/156720507780362137
Source: PubMed

ABSTRACT Insulin modulates cognition and other aspects of normal brain function. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. In addition, insulin resistance increases the risk of age-related memory impairment and Alzheimer's disease. Possible mechanisms through which these risks are increased include the effects of peripheral hyperinsulinemia on memory, CNS inflammation, and regulation of the beta-amyloid peptide. We have shown that raising plasma insulin in humans to levels that characterize patients with insulin resistance increases the levels of Abeta and inflammatory agents in brain. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit a subset of adults with age-related memory impairment and AD.

2 Followers
 · 
158 Views
  • Source
    • "dementia of between 50% and 100% reported (Biessels et al., 2006). Furthermore, AD is associated with peripheral and central nervous system insulin abnormalities with the impaired metabolism of insulin in the brain being closely related to the development of neurodegenerative disorders (Craft, 2007; Hoyer, 2004; Li and Holscher, 2007). While the connection between diabetes, cognitive impairment and aging appears increasingly clear, with some scientists considering AD as a third form of diabetes (Craft, 2012; Steen et al., 2005), the specific mechanisms by which diabetes can affect brain function are not fully understood (Currais et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging represents a major risk factor for numerous illnesses that are of increasing importance to society, including two of the most prevalent: diabetes and Alzheimer's disease. Studies have shown that diabetes is a risk factor for spontaneous Alzheimer's disease. While these studies suggest that diabetes can contribute to Alzheimer's disease, the implications of AD on diabetes are practically unexplored. The major mediator of the pathophysiological effects, the Aß42 peptide, has been shown to enter neurons and lead to an alteration of the intracellular distribution of the molecular motor myosin Vb. Myosin Vb functions in memory and learning by participating in the strengthening of the long-term potentiation (LTP) of synaptic transmissions. It has also been implicated in the translocation of the glucose transporter, GLUT4, to the plasma membrane in response to insulin, a process that is defective in diabetes. Here, the effect on GLUT4 upon entry of the Aß42 peptide into cultured chick retinal neurons was explored. The results suggest an alteration in distribution and a reduced level at the cell surface, as well as an increased colocalization with myosin Vb, which can partially explain the changes in glucose metabolism associated with AD. It is also shown that the presence of the Aß40 peptide inhibits the internalization of the Aß42 peptide in cultured cells. Together, the results provide additional targets for the development of therapeutics against the progression and effects of Alzheimer's disease. Copyright © 2015. Published by Elsevier B.V.
    Brain research 04/2015; DOI:10.1016/j.brainres.2015.04.026 · 2.83 Impact Factor
  • Source
    • "AD is also 47 associated with the desensitization of insulin signaling in 48 the brain (Hoyer, 2004; Craft, 2007; Li and Holscher, 49 2007; Talbot et al., 2012). It seems that the impairment 50 of insulin signaling in the brain may be closely related to 51 the development of neurodegenerative disorders (Hoyer, 52 2004; Holscher, 2005; Craft, 2007; Talbot et al., 2012). 53 Therefore, one of the promising strategies for 54 developing novel AD treatments is to normalize insulin http://dx.doi.org/10.1016/j.neuroscience.2014.02.022 0306-4522/Ó 2014 Published by Elsevier Ltd. on behalf of IBRO. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) have shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. However, the neuroprotective effects of lixisenatide in the brain remain to be clarified. In the present study, we report for the first time the effects of lixisenatide on the amyloid β (Aβ) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Aβ25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Aβ25-35-induced impairments; (3) lixisenatide inhibited the Aβ25-35 injection-induced activation of glycogen synthase kinase 3β (GSK3β), with a significant increase in phosphorylation of ser9 and a significant decrease in phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3β pathway, can prevent Aβ-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD.
    Neuroscience 02/2014; 277. DOI:10.1016/j.neuroscience.2014.02.022 · 3.33 Impact Factor
  • Source
    • "*p < 0.05 vs. control lean mice. reduced insulin levels, insulin receptor expression and insulin resistance in brains of Alzheimer's disease patients (Craft, 2007; Akter et al., 2011). We decided to analyze only young db/db mice to evaluate the SIRT6 variation of expression in the initial stages of type II Diabetes mellitus because prevent cognitive dysfunctions and dementia may possibly occur even in pre-symptomatic stages. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A study was conducted to assess the physiopathological significance of sirtuin 6 (SIRT6) at the brain cortical level. We analyzed the specific expression and subcellular localization of SIRT6 in young db/db mice, an experimental animal model of type II Diabetes mellitus. We analyzed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing db/db mice to lean control mice, examining the six cortical layers and the motor and somatosensory cortex. Finally, we calculated a SIRT6 labeling index. We observed the absence of significant morphological differences between lean and db/db mice, indicating that young db/db mice showed a neuronal morphology and distribution similar to that of lean mice and also normal brain tissue architecture with intact cortical layers. Moreover, sirtuin 6 is mainly localized in the nucleus of both lean and db/db mice. In particular, the db/db mice showed few positive cells compared to lean control mice in all cortical layers. We found a lower sirtuin 6 labeling index without significant differences between the motor and somatosensory cortex. Our findings contribute to further understanding the sirtuin 6 immunohistochemical changes in the early stages of type II Diabetes mellitus and propose its possible implication in the pathogenic processes associated with Diabetes mellitus and diabetes-induced neurodegeneration.
    Acta histochemica 09/2013; 116(1). DOI:10.1016/j.acthis.2013.08.006 · 1.76 Impact Factor
Show more