Peripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo

University of Cologne, Köln, North Rhine-Westphalia, Germany
Diabetes (Impact Factor: 8.1). 01/2006; 54(12):3343-8. DOI: 10.2337/diabetes.54.12.3343
Source: PubMed


Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer's disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. Phospho-FoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.

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Available from: Leona Plum-Mörschel, Nov 19, 2015
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    • "Sonnen et al. [14] demonstrated the AD cases with DM2 had higher levels of cortical IL-6 and greater frequency of microvascular infarcts when compared to AD cases without DM2. Further research by Freude et al. [15] has linked hyperinsulinemia to tau hyperphosphorylation which is an important component in the process underlying AD pathology. Schubert et al. [16] demonstrated that impaired cortical insulin resistance is also linked to tau hyperphosphorylation. Martins et al. [17] also describe several studies implicating neuronal insulin resistance as a precursor to increased amyloid deposition. "
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    ABSTRACT: Background: Past studies investigating the association between Alzheimer's disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE ε4 carriers with AD and DM2 have significantly greater pathology than ApoE ε4 non-carriers. Methods: Data on clinically and pathologically diagnosed Alzheimer's disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 - groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE ε4 carrier status on the neuropathological variables while also accounting for and DM2 status. Results: The DM2+ and DM2 - groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE .ε4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE ε4 carrier status was not significantly associated with DM2 status [.Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE ε4 carriers in relation to DM2+ ApoE ε4 non-carriers. Conclusion: Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4.
    Current Alzheimer research 04/2013; 10(6). DOI:10.2174/15672050113109990006 · 3.89 Impact Factor
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    • "More recently, the same authors demonstrated that impaired IR activity and increased GSK-3β were associated with an increment in P-Tau levels and in senile plaque formation in brains from APP transgenic mice with features of T1D [94]. Freude et al. [32] also found that peripherally-injected insulin directly targets the brain, rapidly initiating IR-mediated signaling pathways that culminate in site-specific tau protein phosphorylation. Similar results were previously obtained in cultured neurons treated with insulin or IGF-1 [95]. "
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    ABSTRACT: According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogues minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.
    Biochimica et Biophysica Acta 01/2013; 1832(4). DOI:10.1016/j.bbadis.2013.01.008 · 4.66 Impact Factor
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    • "[23]–[27]. The regulation of tau is very important, as its dysregulation has been linked to cerebral inflammation and ischemia, as well as insulin resistance [28]–[31]. "
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    ABSTRACT: Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3β) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3β activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3β inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3β with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3β signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM.
    PLoS ONE 10/2012; 7(10):e44117. DOI:10.1371/journal.pone.0044117 · 3.23 Impact Factor
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