Evidence has suggested that insulin resistance (IR) or high levels of glucocorticoids (GCs) may be linked with the pathogenesis and/or progression of Alzheimer's disease (AD). Although studies have shown that a high level of GCs results in IR, little is known about the molecular details that link GCs and IR in the context of AD. Abnormal phosphorylation of tau and activation of μ-calpain are two key events in the pathology of AD. Importantly, these two events are also related with GCs and IR. We therefore speculate that tau phosphorylation and μ-calpain activation may mediate the GCs-induced IR. Akt phosphorylation at Ser-473 (pAkt) is commonly used as a marker for assessing IR. We employed two cell lines, wild-type HEK293 cells and HEK293 cells stably expressing the longest human tau isoform (tau-441; HEK293/tau441 cells). We examined whether DEX, a synthetic GCs, induces tau phosphorylation and μ-calpain activation. If so, we examined whether the DEX-induced tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. The results showed that DEX increased tau phosphorylation and induced tau-mediated μ-calpain activation. Furthermore, pre-treatment with LiCl prevented the effects of DEX on tau phosphorylation and μ-calpain activation. Finally, both LiCl pre-treatment and calpain inhibition prevented the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. In conclusion, our study suggests that the tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation.
References
[1]
Reaven GM (2011) Insulin resistance: the link between obesity and cardiovascular disease. Med Clin North Am 95: 875–892.
[2]
Tsoyi K, Jang HJ, Nizamutdinova IT, Park K, Kim YM, et al. (2010) PTEN differentially regulates expression of ICAM-1 and VCAM-1 through PI3K/Akt/GSK-3β/GATA-6 signaling pathways in TNF-α-activated human endothelial cells. Atherosclerosis 213: 115–121.
[3]
Lu FP, Lin KP, Kuo HK (2009) Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PLoS One 4: e4144.
[4]
Park SA (2011) A common pathogenic mechanism linking type-2 diabetes and Alzheimer's disease: evidence from animal models. J Clin Neurol 7: 10–18.
[5]
Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, et al. (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68: 51–57.
[6]
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, et al. (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69: 29–38.
[7]
Luo D, Hou X, Hou L, Wang M, Xu S, et al. (2011) Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance. Eur J Pharmacol 664: 14–19.
[8]
Hiltunen M, Khandelwal VK, Yaluri N, Tiilikainen T, Tusa M, et al. (2011) Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice. J Cell Mol Med. In press.
[9]
Cao D, Lu H, Lewis T, Li L (2007) Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer Disease. J Bio Chem 282: 36275–36282.
[10]
Ke YD, Delerue F, Gladbach A, Gotz J, Ittner LM (2009) Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. PLoS One 4: e7917.
[11]
Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440: 944–948.
[12]
Harmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser I (1998) Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol Aging 18: 285–289.
[13]
Lupien SJ, Leon MD, Santi SD, Antonio C, Tarshish C, et al. (1998) Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1: 69–73.
[14]
Rissman RA (2009) Stress-induced tau phosphorylation: functional neuroplasticity or neuronal vulnerability? J Alzheim Dis 18: 453–457.
[15]
Congdon EE, Duff KE (2008) Is tau aggregation toxic or protective. J Alzheimers Dis 14: 453–457.
[16]
Gong CX, Grundke-Iqbal I, Iqbal K (2010) Targeting tau protein in Alzheimer's disease. Drugs Aging 27: 351–365.
[17]
Dimakopoulos AC (2005) Protein aggeregation in Alzheimer's disease and other neuropathological disorders. Curr Alzheimer Res 2: 19–28.
[18]
Cowan CM, Bossing T, Page A, Shepherd D, Muhher A (2010) Soluble hyperphosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol 120: 593–604.
[19]
Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 26: 9047–9056.
[20]
Bosco D, Fava A, Plastino M, Montalcini T, Pujia A (2011) Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. J Cell Mol Med 15: 1807–1821.
[21]
Liu Y, Su Y, Sun S, Wang T, Qiao X, et al. (2012) Human tau may modify glucocorticoids-mediated regulation of cAMP-dependent kinase and phosphorylated cAMP response element binding protein. Neurochem Res. Feb 1. [Epub ahead of print].
[22]
Nixon RA (2003) The calpains in aging and aging related disease. Ageing Res Rev 2: 407–418.
[23]
Trinchese F, Fa M, Liu S, Zhang H, Hidalgo A, et al. (2008) Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest 118: 2796–2807.
[24]
Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, et al. (2005) Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280: 37755–37762.
[25]
Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2007) Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. J Neurochem 103: 2462–2470.
[26]
Permut MA, Bernal-Mizrachi E, Inoue H (2000) Calpain 10: the first positional cloning of a gene for type 2 diabetes? J Clin Invest 106: 819–821.
[27]
Derbel S, Doumaguet C, Hubert D, Monsnier-Pudar H, Grabar S, et al. (2006) Calpain 10 and development of diabetes mellitus in cystic fibrosis. J Cyst Fibros 5: 47–51.
[28]
Kang ES, Kim HJ, Nam M, Nam CM, Ahn CW, et al. (2006) A novel 111/121 diplotype in the calpain-10 gene is associated with type 2 diabetes. J Hum Genet 51: 629–633.
[29]
Randriamboavonjy V, Pistrosch F, Bolck B, Schwinger RHG, Dixit M, et al. (2008) Platelet sacroplasmic endoplasmic reticulum Ca2+-ATPase and μ-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Cirrculation 117: 52–60.
[30]
Hsieh YY, Chang CC, Hsu KH, Tsai FJ, Chen CP, et al. (2008) Effect of exercise training on calpain systems in lean and obese Zucker rats. Int J Biol Sci 4: 300–308.
[31]
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signaling pathway in Alzheimer's disease and diabetes. J Pathol 225: 54–82.
[32]
Elliott EM, Mattson MP, Vanderklish P, Lynch G, Chang I, et al. (1993) Corticosterone exacerbates kinate-induced alterations in hippocampal tau immunoreactivity and spectrin proteolysis in vivo. J Neurochem 61: 57–67.
[33]
Smith IJ, Lecker SH, Hasselgren PO (2008) Calpain activity and muscle wasting in sepsis. Endocrinology and metabolism 295: E762–E771.
[34]
Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, et al. (2006) NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Prog Natl Acad Sci USA 103: 2892–2897.
[35]
Ren QG, Liao XM, Chen XQ, Liu GP, Wang JZ (2007) Effects of tau phosphorylation on proeasome activity. FEBS Letters 581: 1521–1528.
[36]
Yu G, Li Y, Tian Q, Liu R, Wang Q, et al. (2011) Berberine attenuates calyculin A-induced cytotoxicity and tau hyperphosphorylation in HEK293 cells. J Alzheimer Dis 24: 525–535.
[37]
Jameson RR, Seidler FJ, Qiao D, Slotkin TA (2006) Adverse neruodevelopmental effects of dexamethasone modeled in PC12 cells: identifying the critical stages and concentration thresholds for the targeting of cell acquisition, differentiation and viability. Neuropsychopharmacology 31: 1647–1658.
[38]
Yaniv SP, Ben-Shachar D, Klein E (2008) Norepinepheine-glucocorticoids interaction does not annul the opposite effects of the individual treatments on celluar plasticity in neuroblastoma cells. Eur J Pharmacol 596: 14–24.
[39]
Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23: 477–501.
[40]
Pfau A, Grossmann C, Freudinger R, Mildenberger S, Benesic A, et al. (2007) Ca but not H2O2 modulates GRE-element activation by the human mineralocorticoid receptor in HEK cells. Mol Cell Endocrinol 264: 35–43.
[41]
Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10: 55–63.
[42]
Caccamo A, Oddo S, Tran LX, LaFerla FM (2007) Lithium reduces tau phosphorylation but not Aβ or working memory deficits in a transgenic model of both plaques and tangles. Am J Pathol 170: 1669–1678.
[43]
Leroy K, Ando K, Heraud C, Yilmaz Z, Authelet M, et al. (2010) Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathlogy. J Alzheim Dis 19: 705–719.
[44]
Szendrei GI, Lee VM, Otvos (1993) Recognition of the minimal epitope of monoclonal antibody Tau-1 depends upon the presence of a phosphate group but not its location. J Neurosci Res 34: 243–249.
[45]
Hong M, Lee VMY (1997) Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 272: 19547–19553.
[46]
Lesort M, Jope RS, Johnson GVW (1999) Insulin transiently increases tau phosphorylation. Involvement of glycogen synthase kinase-3β and Fyn Tyrosine kinase. J Neurochem 72: 576–584.
[47]
Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. (2007) Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27: 13635–13648.
[48]
Cohen P, Goedert M (2004) GSK3 inhibitors: development and therapeutic potential. Nat Rev 3: 479–487.
[49]
Town T, Zolton J, Shaffner R, Schnell B, Crescentini R, et al. (2002) p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J Neurosci Res 69: 362–372.
[50]
Zhang H, Hoff H, Sell C (2003) Downregulation of IRS-1 protein in thapsigargin-treated human prostate epithelial cells. Exp Cell Res 289: 352–358.
[51]
Smith IJ, Dodd SL (2007) Calpain activation causes a proteasome-dependent increase in protein degradation and inhibits the Akt signalling pathway in rat diaphragm muscle. Exp Physiol 92: 561–573.
[52]
Kim B, Feldman EL (2009) Insulin receptor substrate (IRS)-2, but not IRS-1, protects human neuroblastoma cells against apoptosis. Apoptosis 14: 665–673.
[53]
Beltran L, Chaussade C, Vanhaesebroeck B, Cutillas PR (2011) Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity. Proc Natl Acad Sci USA 108: 16217–16222.
[54]
Nolan CJ, Damm P, Prentki M (2011) Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378: 169–181.
[55]
Gallagher EJ, Leroith D, Karnieli E (2011) The metabolic syndrome-from insulin resistance to obesity and diabetes. Med Clin North Am 95: 855–873.
Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, et al. (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 101: 3100–3105.
[58]
Clodfelder-Miller BJ, Zmijewska AA, Johnson GVW, Jope RS (2006) Tau is hyperphophorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes 55: 3320–3325.
[59]
To AW, Ribe EM, Chuang TT, Schroeder JE, Lovestone S (2011) The ε3 and ε4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice. PLoS One 6: e16991.
[60]
Freude S, Plum L, Schnitker J, Leeser U, Udelhoven M, et al. (2005) Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes 54: 3343–3348.
[61]
Lesort M, Johnson GV (2000) Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience 99: 305–316.
[62]
Craft S (2007) Insuln resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 4: 147–152.
[63]
Frisardi V, Solfrizzi V, Capurso C, Imbimbo BP, Vendemiale G, et al. (2010) Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome? J Alzheimers Dis 21: 57–63.
[64]
Riedere RP, Bartl J, Laux G, Grunblatt E (2011) Diatbetes type II: a risk factor for depression-Parkinson-Alzheimer? Neurotox Res 19: 253–265.
[65]
Maccioni RB, Farias G, Morales I, Navarrete L (2010) The revitalized tau hypothesis on Alzheimer's disease. Arch Med Res 41: 226–231.
[66]
Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM (1996) Alterations in tau protein metabolism during normal aging. Dementia 7: 95–103.
[67]
Grundy SM, Brewer HB Jr, Cleeman Jl, Smith SC Jr, Lenfant C, et al. (2004) Definition of metabolic syndrome: report of the National Heart, Lung, and Blood institute/American Heart Association conference on scientific issues related to definition. Circulation 109: 433–438.
[68]
de la Monte SM, Wands JR (2005) Review of insulin and insulin-like growth factor expression, signaling, and malfunctions in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis 7: 45–61.
[69]
Turmer MD, Cassell PG, Hitman GA (2005) Calpain-10: from genome search to function. Diabetes Metab Res Rev 21: 505–514.
[70]
Suzuki K, Hata S, Kawabata Y, Sorimachi H (2004) Structure, activation, and biology of calpain. Diabetes Suppl. 1: S12–S18.
[71]
Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, et al. (2000) A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106: R69–R73.
[72]
Horikawa Y, Oda N, Yu L, Imamura S, Fujiwara K, et al. (2003) Genitic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese. J Clin Endocrinol Metab 88: 244–247.
[73]
Otani K, Polonsky KS, Holloszy JO, Han DH (2006) Inhibition of calpain results in impaired contraction-stimulated GLUT4 translocation in skeletal muscle. Am J Physiol Endocrinol Metab 291: E544–E5E48.
[74]
Sreenan SK, Zhou YP, Otani K, Hansen PA, Currie KP, et al. (2001) Calpains play a role in insulin secretion and action. Diabetes 50: 2013–2020.
[75]
Paul DS, Harmon AW, Winston CP, Patel YM (2003) Calpain facilitaes GLUT4 vesicle translocation during insulin-stimulated glucose uptake in adipocytes. Biochem J 376: 625–632.
[76]
Meier M, Klein HH, Kramer J, Drenckhan M, Schutt M (2007) Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling. J Endorinol 193: 45–51.
[77]
Perrin BJ, Huttenlocher A (2002) Calpain. Int J Biochem Cell Biol 34: 722–725.
[78]
Vega IE, Traverso EE, Ferrer-Acosta Y, Matos E, Colon M, et al. (2008) A novel calcium-binding protein is associated with tau proteins in tauopathy. J Neurochem 106: 96–106.
