Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-3403, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 03/2012; 122(4):1316-38. DOI: 10.1172/JCI59903
Source: PubMed

ABSTRACT While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

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Available from: Konrad Talbot, Sep 29, 2015
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    • "Growing evidence supports the hypothesis that AD is fundamentally a metabolic disease in which brain glucose utilization and energy production are impaired and responsiveness to insulin and insulin-like growth factor (IGF) stimulation [1]. The desensitization of insulin receptors in the brain has been observed in AD patients with Type 2 diabetes (T2DM) [2] [3]. Consistent with these observations, the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance [4], although with variable effects on the brain Amyloid-β protein precursor (AβPP)-Aβ load [5]. "
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    ABSTRACT: Glucagon-like peptide-1 receptor (GLP-1R) agonist treatment has the potential to be a novel therapeutic treatment for Alzheimer's disease (AD). We previously reported that exendin-4, a Gαs protein-coupled GLP-1R agonist, up-regulates the membrane AMPA receptor GluR1 subunit in the neocortex. However, it is uncertain whether GLP-1R agonists have an advantage as an AD treatment target compared with other Gαs protein-coupled receptors. Here we show that both the protein level of proglucagon, a precursor of GLP-1, and the immunoreactivity level of GLP-1 are significantly decreased in the medial prefrontal cortex (mPFC) of aged mice (14 months old) compared with young (3 weeks old) or adult (6 months old) mice, but not in area CA1, the dentate gyrus (DG) nor in the nucleus of the solitary tract. However, the protein and immunoreactivity levels of GLP-1R in the mPFC, DG and hippocampal CA1 and CA3 areas were preserved in the aged mice. We then confirmed whether the age-dependent decrease in GLP-1 in the mPFC was associated with the activity level or the number of microglial cells in the mPFC. Co-staining of CD11b and GLP-1 in the mPFC revealed that the number of CD11b-positive cells was increased in the aged mice. Moreover, lipopolysaccharide (LPS) injection increased the number of CD11b-positive cells in the mPFC, but the number of GLP-1-positive cells was unchanged. However, the number of CD11b-positive cells that co-localized with GLP-1R in the mPFC is increased by LPS and aging. Because the GLP-1R is preserved in aged mPFC, but the amount of GLP-1 produced in the brain region is diminished, and spatial cognitive memory was impaired in aged mice, we propose that treatment with GLP-1 analogues has great promise for rescuing and ameliorating the age-related mPFC-dependent decline of cognitive functions.
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    • "Phosphorylation of the insulin receptor β chain was reduced at positions IRβ pY1150/1151 and IRβ pY960, while the insulin receptor substrate 1 (IRS-1) was hyperphosphorylated at positions IRS-1 pS616 and IRS-1 pS636. Furthermore, when incubating AD brain tissue with insulin, it revealed a reduced downstream second messenger cascade (Talbot et al., 2012). Incubating the brain tissue with the GLP-1 mimetic liraglutide also reversed some of the insulin signaling impairments (Talbot et al., 2011). "
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    ABSTRACT: Type 2 diabetes is a risk factor for Alzheimer’s disease and Parkinson’s disease. Insulin signaling in the brains of people with Alzheimer’s disease or Parkinson’s disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alzheimer’s disease and Parkinson’s disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer’s disease and Parkinson’s disease. On the basis of these promising findings, several clinical trials are ongoing with the first encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer’s disease and Parkinson’s disease that are currently unavailable.
    Neural Regeneration Research 11/2014; 9(21):1870-1873. DOI:10.4103/1673-5374.145342 · 0.22 Impact Factor
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    • "Insulin signaling is also altered by Aβ. In the AD brain, the levels of insulin and IGF (113) and the responses to insulin and IGF (114) are reduced. The levels and activities of the insulin signaling pathway are also decreased in AD (81, 115) and diabetic brains (81), as mentioned above. "
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    ABSTRACT: Emerging evidence suggests that diabetes affects cognitive function and increases the incidence of dementia. However, the mechanisms by which diabetes modifies cognitive function still remains unclear. Morphologically, diabetes is associated with neuronal loss in the frontal and temporal lobes including the hippocampus, and aberrant functional connectivity of the posterior cingulate cortex and medial frontal/temporal gyrus. Clinically, diabetic patients show decreased executive function, information processing, planning, visuospatial construction, and visual memory. Therefore, in comparison with the characteristics of AD brain structure and cognition, diabetes seems to affect cognitive function through not only simple AD pathological feature-dependent mechanisms but also independent mechanisms. As an Aβ/tau-independent mechanism, diabetes compromises cerebrovascular function, increases subcortical infarction, and might alter the blood-brain barrier. Diabetes also affects glucose metabolism, insulin signaling, and mitochondrial function in the brain. Diabetes also modifies metabolism of Aβ and tau and causes Aβ/tau-dependent pathological changes. Moreover, there is evidence that suggests an interaction between Aβ/tau-dependent and independent mechanisms. Therefore, diabetes modifies cognitive function through Aβ/tau-dependent and independent mechanisms. Interaction between these two mechanisms forms a vicious cycle.
    Frontiers in Endocrinology 09/2014; 5:143. DOI:10.3389/fendo.2014.00143
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