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Vol. 90, No. 4, 2009
Issue release date: November 2009
Neuroendocrinology 2009;90:383–390

Plasma Amyloid-β Peptide Levels Correlate with Adipocyte Amyloid Precursor Protein Gene Expression in Obese Individuals

Lee Y.-H. · Martin J.M. · Maple R.L. · Tharp W.G. · Pratley R.E.
Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine, Burlington, Vt., USA

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Background/Aims: Several studies have demonstrated that midlife obesity increases the risk for dementia and Alzheimer’s disease. Moreover, plasma 42-amino-acid amyloid-β (Aβ42) levels appear to correlate with BMI. We recently demonstrated that adipocyte amyloid precursor protein (APP) expression is upregulated in obesity and correlates with insulin resistance and adipose tissue inflammation. In this study, we aimed to investigate the relation between adipocyte APP expression and plasma Aβ peptide levels. Methods: We conducted a pilot study in which we measured adipocyte APP gene expression and the circulating plasma levels of Aβ40 in 10 obese individuals before and after a 6-month behaviorally based weight loss intervention. Subjects had an oral glucose tolerance test with measurement of insulin levels, Aβ40 levels measured by ELISA and transcript levels of APP in subcutaneous abdominal adipocytes measured by quantitative real-time PCR. Results: At baseline, adipocyte APP expression correlated significantly with plasma Aβ40 levels and with 2-hour insulin concentrations. Following the 6-month weight loss intervention, body weight and BMI decreased significantly. Fasting plasma concentrations of glucose and insulin were improved. Adipocyte APP expression was significantly decreased (p < 0.001) after weight loss. Changes in adipocyte APP expression correlated with changes in plasma Aβ40 levels (R = 0.74, p = 0.01) and changes in 2-hour insulin (R = 0.75, p = 0.01). Conclusion: The results of this pilot study suggest that increased circulating plasma levels of Aβ peptides in obesity may be due to increased adipocyte APP gene expression. While these results suggest a possible mechanism linking midlife obesity with the later development of Alzheimer’s disease, further research is necessary to elucidate the regulation and functional significance of APP in adipocytes.

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  1. Mattson MP: Pathways towards and away from Alzheimer’s disease. Nature 2004;430:631–639.
  2. Gandy S: The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest 2005;115:1121–1129.
  3. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  4. Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science 2002;298:789–791.
  5. White JA, Manelli AM, Holmberg KH, Van Eldik LJ, Ladu MJ: Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis 2005;18:459–465.
  6. Butterfield DA, Griffin S, Munch G, Pasinetti GM: Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer’s disease brain exists. J Alzheimers Dis 2002;4:193–201.
  7. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE: Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci 2000;20:558–567.
  8. Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM Jr, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J: Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia 2001;35:72–79.
  9. Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, Oltersdorf T: Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci USA 1988;85:7341–7345.
  10. Zheng H, Koo EH: The amyloid precursor protein: beyond amyloid. Mol Neurodegener 2006;1:5.
  11. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733–736.
  12. Palmert MR, Golde TE, Cohen ML, Kovacs DM, Tanzi RE, Gusella JF, Usiak MF, Younkin LH, Younkin SG: Amyloid protein precursor messenger RNAs: differential expression in Alzheimer’s disease. Science 1988;241:1080–1084.
  13. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, et al: Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 1992;258:126–129.
  14. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, et al: Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322–325.
  15. Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA: Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci USA 1993;90:2092–2096.
  16. Jensen M, Schroder J, Blomberg M, Engvall B, Pantel J, Ida N, Basun H, Wahlund LO, Werle E, Jauss M, Beyreuther K, Lannfelt L, Hartmann T: Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer’s disease and declines with disease progression. Ann Neurol 1999;45:504–511.
  17. Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, Rosand J, Growdon JH, Greenberg SM: Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 2006;66:23–29.
  18. Irizarry MC: Biomarkers of Alzheimer disease in plasma. NeuroRx 2004;1:226–234.
  19. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996;2:864–870.
  20. Fukumoto H, Tennis M, Locascio JJ, Hyman BT, Growdon JH, Irizarry MC: Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels. Arch Neurol 2003;60:958–964.
  21. Ertekin-Taner N, Younkin LH, Yager DM, Parfitt F, Baker MC, Asthana S, Hutton ML, Younkin SG, Graff-Radford NR: Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology 2008;70:596–606.
  22. Van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM: Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 2006;5:655–660.
  23. Gorospe EC, Dave JK: The risk of dementia with increased body mass index. Age Ageing 2007;36:23–29.
  24. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I: An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003;163:1524–1528.
  25. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K: Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 2005;330:1360.
  26. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A: Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556–1560.
  27. Razay G, Vreugdenhil A, Wilcock G: Obesity, abdominal obesity and Alzheimer disease. Dement Geriatr Cogn Disord 2006;22:173–176.
  28. Rosengren A, Skoog I, Gustafson D, Wilhelmsen L: Body mass index, other cardiovascular risk factors, and hospitalization for dementia. Arch Intern Med 2005;165:321–326.
  29. Luchsinger JA, Mayeux R: Adiposity and Alzheimer’s disease. Curr Alzheimer Res 2007;4:127–134.
  30. Balakrishnan K, Verdile G, Mehta PD, Beilby J, Nolan D, Galvao DA, Newton R, Gandy SE, Martins RN: Plasma Abeta42 correlates positively with increased body fat in healthy individuals. J Alzheimers Dis 2005;8:269–282.
  31. Lee YH, Nair S, Rousseau E, Allison DB, Page GP, Tataranni PA, Bogardus C, Permana PA: Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Diabetologia 2005;48:1776–1783.
  32. Nair S, Lee YH, Rousseau E, Cam M, Tataranni PA, Baier LJ, Bogardus C, Permana PA: Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians. Diabetologia 2005;48:1784–1788.
  33. Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE: Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring) 2008;16:1493–1500.
  34. Lee YH, Tharp WG, Peshavaria M, Nair S, Permana PA, Pratley RE: Overexpression of amyloid precursor protein (app) in adipose tissue of obese individuals. Obesity 2006;13:A214.
  35. Lee YH, Tokraks S, Pratley RE, Bogardus C, Permana PA: Identification of differentially expressed genes in skeletal muscle of non-diabetic insulin-resistant and insulin-sensitive Pima Indians by differential display PCR. Diabetologia 2003;46:1567–1575.
  36. Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, Schwartz MW, Plymate S, Craft S: Insulin increases CSF Abeta42 levels in normal older adults. Neurology 2003;60:1899–1903.
  37. Chen M, Inestrosa NC, Ross GS, Fernandez HL: Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun 1995;213:96–103.
  38. Galloway S, Jian L, Johnsen R, Chew S, Mamo JC: Beta-amyloid or its precursor protein is found in epithelial cells of the small intestine and is stimulated by high-fat feeding. J Nutr Biochem 2007;18:279–284.
  39. Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A: Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 2003;63:7032–7037.
  40. Kuo YM, Kokjohn TA, Watson MD, Woods AS, Cotter RJ, Sue LI, Kalback WM, Emmerling MR, Beach TG, Roher AE: Elevated Abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol 2000;156:797–805.
  41. Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG: Expression of beta amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer’s disease using PCR. Neuron 1990;4:253–267.
  42. Leahey TM, Myers TA, Gunstad J, Glickman E, Spitznagel MB, Alexander T, Juvancic-Heltzel J: Abeta40 is associated with cognitive function, body fat and physical fitness in healthy older adults. Nutr Neurosci 2007;10:205–209.
  43. Gasparini L, Netzer WJ, Greengard P, Xu H: Does insulin dysfunction play a role in Alzheimer’s disease? Trends Pharmacol Sci 2002;23:288–293.
  44. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr: Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998;50:164–168.
  45. Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Vanhanen M, Hanninen T, Kervinen K, Kesaniemi YA, Riekkinen PJ, Laakso M: Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 1997;315:1045–1049.
  46. Peila R, Rodriguez BL, White LR, Launer LJ: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004;63:228–233.
  47. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB: The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004;292:2237–2242.
  48. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S, Zöchling R, Boissl KW, Jellinger K, Riederer P: Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 1998;105:423–438.
  49. Hoyer S: Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 1998;105:415–422.
  50. Odetti P, Piccini A, Giliberto L, Borghi R, Natale A, Monacelli F, Marchese M, Assini A, Colucci M, Cammarata S, Tabaton M: Plasma levels of insulin and amyloid beta 42 are correlated in patients with amnestic mild cognitive impairment. J Alzheimers Dis 2005;8:243–245.
  51. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S: Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005;62:1539–1544.
  52. Lyon CJ, Law RE, Hsueh WA: Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:2195–2200.
  53. Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–2556.
  54. Rajala MW, Scherer PE: Minireview: the adipocyte – at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 2003;144:3765–3773.
  55. Lee YH, Pratley RE: The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep 2005;5:70–75.
  56. Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H: Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001;21:2561–2570.
  57. Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M: Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J 2000;14:1015–1022.
  58. Phiel CJ, Wilson CA, Lee VM, Klein PS: GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003;423:435–439.
  59. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100:4162–4167.
  60. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ: Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998;273:32730–32738.
  61. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R: Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 2002;22:RC221.
  62. Klaus S, Keijer J: Gene expression profiling of adipose tissue: individual, depot-dependent, and sex-dependent variabilities. Nutrition 2004;20:115–120.
  63. Soukas A, Socci ND, Saatkamp BD, Novelli S, Friedman JM: Distinct transcriptional profiles of adipogenesis in vivo and in vitro. J Biol Chem 2001;276:34167–34174.

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