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Amyloid Beta-Derived Diffusible Ligands (ADDLs) Induce Abnormal Expression of Insulin Receptors in Rat Hippocampal Neurons

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Abstract

Amyloid beta (Aβ) is an important pathogenic factor in Alzheimer’s disease (AD). In this study, we investigated the hypothesis that administration of amyloid-derived diffusible ligands (ADDLs) prepared from a synthetic Aβ 1-42 amyloid peptide can cause defective expression of insulin receptors (IRs). To this end, primary rat hippocampal neurons were treated with various concentrations of ADDLs and expression levels of IRs were measured using real-time PCR and western blots. In these experiments, the expression of IRs significantly increased following treatment with low concentrations of Aβ 1-42. In contrast, when higher concentrations of Aβ 1-42 were applied, the number of apoptotic cells present increased, and expression of IRs significantly decreased. In combination, these results suggest that ADDLs is able to induce abnormal expression of IRs and interrupt normal insulin signaling, thereby potentially contributing to central insulin resistance that can occur during progression of AD.

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Abbreviations

ADDLs:

Amyloid beta-derived diffusible ligands

Aβ :

Amyloid beta

AD:

Alzheimer’s disease

IRs:

Insulin receptors

References

  • Bourdel-Marchasson I, Lapre E, Laksir H, Puget E (2010) Insulin resistance, diabetes and cognitive function: consequences for preventative strategies. Diabetes Metab 36:173–181

    Article  CAS  PubMed  Google Scholar 

  • Craft S (2007) Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 4:147–152

    Article  CAS  PubMed  Google Scholar 

  • DaRocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Sereno L, Rodriguez M, Sanchez B, Hyman BT, Gomez-Isla T (2011) Brain oligomeric beta-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol 70:360–376

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, Holtzman DM (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65:176–183

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zochling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 105:423–438

    Article  CAS  PubMed  Google Scholar 

  • Frolich L, Blum-Degen D, Riederer P, Hoyer S (1999) A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci 893:290–293

    Article  CAS  PubMed  Google Scholar 

  • Garg S, Timm T, Mandelkow EM, Mandelkow E, Wang Y (2011) Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment. Neurobiol Aging 32:1–14

    Article  CAS  PubMed  Google Scholar 

  • Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM, Zanetti O, Guralnik JM, Ferrucci L (2005) Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 62:1067–1072

    Article  PubMed  Google Scholar 

  • Hernandez F, Gomez de Barreda E, Fuster-Matanzo A, Lucas JJ, Avila J (2010) GSK3: a possible link between beta amyloid peptide and tau protein. Exp Neurol 223:322–325

    Article  CAS  PubMed  Google Scholar 

  • Hoyer S (2000) Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp Gerontol 35:1363–1372

    Article  CAS  PubMed  Google Scholar 

  • Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108:5819–5824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Joachim CL, Selkoe DJ (1992) The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease. Alzheimer Dis Assoc Disord 6:7–34

    Article  CAS  PubMed  Google Scholar 

  • Jordan J, Galindo MF, Miller RJ, Reardon CA, Getz GS, LaDu MJ (1998) Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci 18:195–204

    CAS  PubMed  Google Scholar 

  • Kar S, Chabot JG, Quirion R (1993) Quantitative autoradiographic localization of [125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 333:375–397

    Article  CAS  PubMed  Google Scholar 

  • Ling X, Martins RN, Racchi M, Craft S, Helmerhorst E (2002) Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor. J Alzheimers Dis 4:369–374

    CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Marks JL, Porte D Jr, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127:3234–3236

    Article  CAS  PubMed  Google Scholar 

  • Mosconi L, Mistur R, Switalski R, Brys M, Glodzik L, Rich K, Pirraglia E, Tsui W, De Santi S, de Leon MJ (2009) Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology 72:513–520

    Article  CAS  PubMed  Google Scholar 

  • Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199:265–273

    Article  CAS  PubMed  Google Scholar 

  • Plaschke K, Kopitz J, Siegelin M, Schliebs R, Salkovic-Petrisic M, Riederer P, Hoyer S (2010) Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes in Tg2576 AbetaPP-overexpressing mice. J Alzheimers Dis 19:691–704

    CAS  PubMed  Google Scholar 

  • Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  • Resende R, Ferreiro E, Pereira C, Resende de Oliveira C (2008) Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1–42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death. Neuroscience 155:725–737

    Article  CAS  PubMed  Google Scholar 

  • Rhein V, Eckert A (2007) Effects of Alzheimer's amyloid-beta and tau protein on mitochondrial function – role of glucose metabolism and insulin signalling. Arch Physiol Biochem 113:131–141

    Article  CAS  PubMed  Google Scholar 

  • Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD, Rosiglitazone in Alzheimer's Disease Study, G (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6:246–254

    CAS  PubMed  Google Scholar 

  • Schrag M, Sharma S, Brown-Borg H, Ghribi O (2008) Hippocampus of Ames dwarf mice is resistant to beta-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels. Hippocampus 18:239–244

    Article  CAS  PubMed  Google Scholar 

  • Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes? J Alzheimers Dis 7:63–80

    CAS  PubMed  Google Scholar 

  • Takeda S, Sato N, Rakugi H, Morishita R (2011) Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol Biosyst 7:1822–1827

    Article  CAS  PubMed  Google Scholar 

  • Townsend M, Mehta T, Selkoe DJ (2007) Soluble Aβ inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Zheng W, Xie JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46

    Article  PubMed Central  PubMed  Google Scholar 

  • Yankner BA, Lu T (2009) Amyloid beta-protein toxicity and the pathogenesis of Alzheimer disease. J Biol Chem 284:4755–4759

    Article  CAS  PubMed  Google Scholar 

  • Youssef I, Florent-Bechard S, Malaplate-Armand C, Koziel V, Bihain B, Olivier JL, Leininger-Muller B, Kriem B, Oster T, Pillot T (2008) N-truncated amyloid-beta oligomers induce learning impairment and neuronal apoptosis. Neurobiol Aging 29:1319–1333

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The funding of this research was supported by a key project grant from the Natural Science foundation of Heilongjiang Province, China (No: ZJY0706).

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The authors declare that there are no conflicts of interest.

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Correspondence to Yina Zhang.

Additional information

Xin Liu and Zongyan Teng contributed to this work equally.

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Liu, X., Teng, Z., Cui, C. et al. Amyloid Beta-Derived Diffusible Ligands (ADDLs) Induce Abnormal Expression of Insulin Receptors in Rat Hippocampal Neurons. J Mol Neurosci 52, 124–130 (2014). https://doi.org/10.1007/s12031-013-0216-0

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  • DOI: https://doi.org/10.1007/s12031-013-0216-0

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