2016, Number 2
<< Back Next >>
Rev Invest Clin 2016; 68 (2)
The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer´s Disease
Arrieta-Cruz I, Gutiérrez-Juárez R
Language: English
References: 58
Page: 53-58
PDF size: 102.97 Kb.
ABSTRACT
Alzheimer´s disease is a chronic neurodegenerative disorder affecting millions of people worldwide, characterized by a progressive
decline in cognitive functions. Factors involved in the pathogenesis of Alzheimer´s disease include metabolic alterations such as
insulin resistance and hyperglycemia, both of which are also hallmarks of type-2 diabetes mellitus. The accumulation of β-amyloid
peptides in the brain of Alzheimer´s patients is responsible in part for the neurotoxicity underlying the loss of synaptic plasticity
that triggers a cascade of events leading to cell death. A large number of studies revealed the key role of the hippocampus and
cerebral cortex in the memory and learning deficits of Alzheimer´s disease. Although ample evidence suggests a link between
altered insulin action, the dysregulation of glucose metabolism, and β-amyloid accumulation in animal models and humans with
Alzheimer´s, no supporting evidence was available. In this article, we review the potential toxic effects of β-amyloid in the
hypothalamus, a brain center involved in the control of insulin action and glucose metabolism. Furthermore, we discuss our
recent studies unraveling a novel neurotoxic action of β-amyloid that perturbs hypothalamic glucoregulation, leading to increased
hepatic glucose production and hyperglycemia. These findings provide evidence for a link between β-amyloid toxicity and altered
glucose metabolism.
REFERENCES
Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741-66.
LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci. 2007;8:499-509.
Mi K, Johnson GV. The role of tau phosphorylation in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res. 2006; 3:449-63.
Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258:126-9.
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDAtype glutamate receptor-dependent signaling pathway. J Neurosci. 2007;27:2866-75.
Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci. 2010;13:190-6.
Jacobsen JS, Wu CC, Redwine JM, et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:5161-6.
Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML. Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol. 2004;33:377-87.
Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004;7:1181-3.
Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837-42.
Shankar GM, Walsh DM. Alzheimer’s disease: synaptic dysfunction and Abeta. Mol Neurodegener. 2009;4:48.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184-5.
Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6:487-98.
Nitta A, Fukuta T, Hasegawa T, Nabeshima T. Continuous infusion of beta-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol. 1997;73:51-7.
Itoh A, Akaike T, Sokabe M, et al. Impairments of long-term potentiation in hippocampal slices of beta-amyloid-infused rats. Eur J Pharmacol. 1999;382:167-75.
Itoh A, Nitta A, Nadai M, et al. Dysfunction of cholinergic and dopaminergic neuronal systems in beta-amyloid protein--infused rats. J Neurochem. 1996;66:1113-7.
Nag S, Yee BK, Tang F. Reduction in somatostatin and substance P levels and choline acetyltransferase activity in the cortex and hippocampus of the rat after chronic intracerebroventricular infusion of beta-amyloid (1-40). Brain Res Bull. 1999;50:251-62.
Chen SY, Wright JW, Barnes CD. The neurochemical and behavioral effects of beta-amyloid peptide(25-35). Brain Res. 1996; 720:54-60.
O’Hare E, Weldon DT, Mantyh PW, et al. Delayed behavioral effects following intrahippocampal injection of aggregated A beta (1-42). Brain Res. 1999;815:1-10.
Sweeney WA, Luedtke J, McDonald MP, Overmier JB. Intrahippocampal injections of exogenous beta-amyloid induce postdelay errors in an eight-arm radial maze. Neurobiol Learn Mem. 1997;68:97-101.
Ikeda S, Allsop D, Glenner GG. Morphology and distribution of plaque and related deposits in the brains of Alzheimer’s disease and control cases. An immunohistochemical study using amyloid beta-protein antibody. Lab Invest. 1989;60:113-22.
Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Ihara Y. A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated by beta protein immunostaining. Acta Neuropathol. 1988;76:541-9.
Standaert DG, Lee VM, Greenberg BD, Lowery DE, Trojanowski JQ. Molecular features of hypothalamic plaques in Alzheimer’s disease. Am J Pathol. 1991;139:681-91.
Saper CB, German DC. Hypothalamic pathology in Alzheimer’s disease. Neurosci Lett. 1987;74:364-70.
Simpson J, Yates CM, Watts AG, Fink G. Congo red birefringent structures in the hypothalamus in senile dementia of the Alzheimer type. Neuropathol Appl Neurobiol. 1988;14:381-93.
Baskin DG, Figlewicz LD, Seeley RJ, Woods SC, Porte D, Schwartz MW. Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res. 1999;848: 114-23.
Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404: 661-71.
Arrieta-Cruz I, Su Y, Knight CM, Lam TK, Gutierrez-Juarez R. Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats. Diabetes. 2013;62: 1152-8.
Su Y, Lam TK, He W, et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes. 2012;61:85-93.
Liu L, Karkanias GB, Morales JC, et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem. 1998;273:31160-7.
Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002;8:1376-82.
Pocai A, Lam TK, Gutierrez-Juarez R, et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434: 1026-31.
Inoue H, Ogawa W, Asakawa A, et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 2006;3:267-75.
Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24:855-72.
Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol. 1991;36:343-62.
Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000; 289:2122-5.
Burks DJ, Font de MJ, Schubert M, et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature. 2000; 407:377-82.
Christie JM, Wenthold RJ, Monaghan DT. Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. J Neurochem. 1999;72:1523-8.
Lin JW, Ju W, Foster K, et al. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci. 2000;3:1282-90.
Wan Q, Xiong ZG, Man HY, et al. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature. 1997;388:686-90.
Park CR. Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev. 2001;25:311-23.
Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001;177:125-34.
Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998;112:1199-208.
Frolich L, Blum-Degen D, Bernstein HG, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm (Vienna). 1998;105:423-38.
Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR. Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol Cell Biol. 2008; 28: 6314-28.
Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem. 1997;272:19547-53.
Lesort M, Johnson GV. Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience. 2000;99: 305-16.
Gasparini L, Gouras GK, Wang R, et al. Stimulation of betaamyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21:2561-70.
Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid- beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging. 2006;27:190-8.
Arrieta-Cruz I, Knight CM, Gutierrez-Juarez R. Acute exposure of the mediobasal hypothalamus to amyloid-beta25-35 perturbs hepatic glucose metabolism. J Alzheimers Dis. 2015;46: 843-8.
Leibson CL, Rocca WA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145:301-8.
Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011;77:1126-34.
Ott A, Stolk RP, van HF, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999;53:1937-42.
Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep. 2007;7:373-80.
Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50:164-8.
Craft S, Dagogo-Jack SE, Wiethop BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neurosci. 1993;107: 926-40.
Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging. 1996;17:123-30.
Craft S, Asthana S, Newcomer JW, et al. Enhancement of memory in Alzheimer’s disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry. 1999;56:1135-40.