Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains

Journal of Neuroinflammation

Gary L Wenk¹  Sarah C Hopp¹  Sarah E Royer¹  Roxanne M Kaercher²  Alexis M Crockett¹  Heather M D’Angelo²  Ashley E Lynn¹  Linda Adzovic¹ 

[1] Department of Neuroscience, Ohio State University, Columbus 43210, OH, USA;Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus 43210, OH, USA

关键词: Memory;    Insulin;    Inflammation;    Rat;    LPS;    Aging;   

Others  :  1227102
DOI  :  10.1186/s12974-015-0282-z

 received in 2014-12-02, accepted in 2015-03-17,  发布年份 2015

【 摘 要 】

The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain.

【 授权许可】

   
2015 Adzovic et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cooper NR, et al.: Inflammation in Alzheimer’s disease. Neurobiol Aging 2000, 21:383-421.
• [2]Lynch AM, Lynch MA: The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 2002, 15:1779-88.
• [3]Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B: Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 2009, 87:2484-97.
• [4]Ye SM, Johnson RW: Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 1999, 9:139-48.
• [5]Colton C, Wilcock DM: Assessing activation states in microglia. CNS Neurol Disord Drug Targets 2010, 9:174-91.
• [6]Smith JA, Das A, Ray SK, Banik NL: Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 2012, 87:10-20.
• [7]Wenk GL, Hauss-Wegrzyniak B: Animal models of chronic neuroinflammation as a model of Alzheimer’s disease. In Inflammatory events in neurodegeneration. Edited by Bondy S, Campbell A. Prominent Press, Scottsdale, AZ; 2001:83-7.
• [8]Bilbo SD: Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline. Neurobiol Learn Mem 2010, 94:57-64.
• [9]Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA: Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer’s disease. Neurodegener Dis 2010, 7:38-41.
• [10]Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, et al.: Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A 2010, 107:6058-63.
• [11]Watson GS, Craft S: Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 2004, 490:97-113.
• [12]Arnold SE, Arvanitakis Z, Bakshi KP, Bennett DA, Fuino RL, Han LY: Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012, 122:1316-38.
• [13]Najem D, Bamji-Mirza M, Chang N, Liu QY, Zhang W: Insulin resistance, neuroinflammation, and Alzheimer’s disease. Rev Neurosci 2014, 25:509-25.
• [14]Jeschke MG, Klein D, Bolder U, Einspanier R: Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinol 2004, 145:4084-93.
• [15]Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, et al.: Insulin inhibits intranuclear nuclear factor κB and stimulates IκB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001, 86:3257-65.
• [16]Leverence JT, Medhora M, Konduri GG, Sampath V: Lipopolysaccharide-induced cytokine expression in alveolar epithelial cells: role of PKCζ-mediated p47phox phosphorylation. Chemico-Biol Inter 2011, 189:72-81.
• [17]Dallot E, Méhats C, Oger S, Leroy MJ, Breuiller-Fouché MA: Role for PKCζ in the LPS-induced translocation NF-κB p65 subunit in cultured myometrial cells. Biochimie 2005, 87:513-21.
• [18]Li H, Liu B, Huang J, Chen H, Guo X, Yuan Z: Insulin inhibits lipopolysaccharide-induced nitric oxide synthase expression in rat primary astrocytes. Brain Res 2013, 1506:1-11.
• [19]Martins JO, Ferracini M, Ravanelli N, Landgraf RG, Jancar S: Insulin suppresses LPS-induced iNOS and COX-2 expression and NF-κB activation in alveolar macrophages. Cell Physiol Biochem 2008, 22:279-86.
• [20]Huang XH, Doerner AM, Pan WW, Smith L, Huang S, Papdimor TJ, et al.: An atypical protein kinase C (PKCζ) plays a critical role in lipopolysaccharide-activated NF-κB in human peripheral blood monocytes and macrophages. J Immunol 2009, 182:5810-5.
• [21]Aye IL, Jansson T, Powell TL: Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system amino acid transport in primary human trophoblasts. Mol Cell Endocrinol 2013, 381:46-55.
• [22]Gual P, Le Marchand-Brustel Y, Tanti JF: Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005, 87:99-109.
• [23]Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C, White MF: IRS1 serine 307 promotes insulin sensitivity in mice. Cell Metab 2010, 11:84-92.
• [24]Balakrishnan K, Verdile G, Mehta PD, Beilby J, Nolan D, Galvao DA, et al.: Plasma Aβ42 correlates positively with increased body fat in healthy individuals. J Alz Dis 2005, 8:269-82.
• [25]Biessels G, Kappelle LJ: Increased risk of Alzheimer’s disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 2005, 33:1041-4.
• [26]Casserly I, Topol E: Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004, 363:1139-46.
• [27]De Felice FG: Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 2013, 123:531-9.
• [28]Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY: Risk of Alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiol 2012, 38:237-44.
• [29]Havrankova J, Roth J, Brownstein M: Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978, 272:827-9.
• [30]Zhao WQ, Alkon DL: Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001, 177:125-34.
• [31]Clarke DW, Mudd L, Boyd FT Jr: Insulin is released from rat brain neuronal cells in culture. J Neurochem 1986, 47:831-6.
• [32]Valenciano AI, Corrochano S, de Pablo F, de la Villa P, de la Rosa EJ: Proinsulin/insulin is synthesized locally and prevents caspase- and cathepsin-mediated cell death in the embryonic mouse retina. J Neurochem 2006, 99:524-36.
• [33]Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ: Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn Mem 2005, 12:646-55.
• [34]Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL: Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002, 5:514-6.
• [35]Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al.: Intranasal insulin improves memory in humans. Psychoneuroendocrinol 2004, 29:1326-34.
• [36]Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, et al.: Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurol 2008, 70:440-8.
• [37]Adzovic L, Domenici L: Insulin induces phosphorylation of the AMPA receptor subunit GluR1, reversed by ZIP, and overexpression of protein kinase M zeta, reversed by amyloid beta. J Neurochem 2014, 31:582-7.
• [38]Kamal A, Ramakers GM, Gispen WH, Biessels GJ: Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons. Brain Res 2012, 1435:99-104.
• [39]Marchalant Y, Cerbai F, Brothers H, Wenk GL: Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol Aging 2008, 29:1894-901.
• [40]Marchalant Y, Brothers HM, Norman GJ, Karolina K, DeVries C, Wenk GL: Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis 2009, 34:300-7.
• [41]Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL: Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res 1998, 780:294-303.
• [42]Hauss-Wegrzyniak B, Galons JP, Wenk GL: Quantitative volumetric analysis of brain magnetic resonance imaging from rat with chronic neuroinflammation and correlation with histology. Exp Neurol 2000, 165:347-54.
• [43]Hauss-Wegrzyniak B, Lynch MA, Vraniak PD, Wenk GL: Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp Neurol 2002, 341:336-41.
• [44]Rosi S, Ramirez-Amaya V, Hauss-Wegrzyniak B, Wenk GL: Chronic brain inflammation leads to a decline in hippocampal NMDA R1 receptors. J Neuroinflam 2004, 1:12-8. BioMed Central Full Text
• [45]Rosi S, Ramirez-Amaya V, Vazdarjanova A, Esperanza E, Larkin P, Fike JR, et al.: Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine. Brain 2009, 132:2464-86.
• [46]Rosi S, Ramirez-Amaya V, Vazdarjanova A, Worley PF, Barnes CA, Wenk GL: Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression. J Neurosci 2005, 25:723-31.
• [47]Wenk GL, Hauss-Wegrzyniak B, Willard LB: Pathological and biochemical studies of chronic neuroinflammation may lead to therapies for Alzheimer’s disease. In Research and perspectives in neurosciences: neuro-immune neurodegenerative and psychiatric disorders and neural injury. Edited by Patterson P, Kordon C, Christen Y. Springer-Verlag, Heidelberg; 2000:73-7.
• [48]Marchalant Y, Rosi S, Wenk GL: Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. Neurosci 2007, 144:1516-22.
• [49]Figlewicz DP, Bennett J, Evans SB, Kaiyala K, Sipols AJ, Benoit SC: Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats. Behav Neurosci 2004, 118:479-87.
• [50]Bardou I, Brothers HM, Kaercher RM, Hopp SC, Wenk GL: Differential effects of duration and age upon the consequences of neuroinflammation in the hippocampus. Neurobiol Aging 2013, 34:2293-301.
• [51]Martins JO, Ferracini M, Ravanelli N, Landgraf RG, Jancar S: Insulin inhibits LPS-induced signaling pathways in alveolar macrophages. Cell Physiol Biochem 2007, 21:297-304.
• [52]Bamji-Mirza M, Callaghan D, Najem D, Shen S, Hasim MS, Yang Z, et al.: Stimulation of insulin signaling and inhibition of JNK-AP1 activation protect cells from amyloid-β-induced signaling dysregulation and inflammatory response. J Alz Dis 2014, 40:105-22.
• [53]Brothers HM, Bardou I, Hopp SC, Kaercher RM, Corona AW, Fenn AM, et al.: Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory. J Neuroimm Pharmacol 2013, 8:1098-105.
• [54]Leitges M, Sanz L, Martin P, Duran A, Braun U, García JF, et al.: Targeted disruption of the zeta PKC gene results in the impairment of the NF-κB pathway. Mol Cell 2001, 8:771-80.
• [55]Frölich L, Blum–Degen D, Bernstein HG, Englesberger S, Humrich J, Laufer S, et al.: Insulin and insulin receptors in the brain in aging and in sporadic Alzheimer’s disease. J Neural Transm 1998, 105:423-38.
• [56]Townsend M, Metha T, Selkoe DJ: Soluble A-beta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 2007, 282:33305-12.