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Progressive Neuronal Pathology and Synaptic Loss Induced by Prediabetes and Type 2 Diabetes in a Mouse Model of Alzheimer’s Disease

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Abstract

Age remains the main risk factor for developing Alzheimer’s disease (AD) although certain metabolic alterations, including prediabetes and type 2 diabetes (T2D), may also increase this risk. In order to understand this relationship, we have studied an AD-prediabetes mouse model (APP/PS1) with severe hyperinsulinemia induced by long-term high fat diet (HFD), and an AD-T2D model, generated by crossing APP/PS1 and db/db mice (APP/PS1xdb/db). In both, prediabetic and diabetic AD mice, we have analyzed underlying neuronal pathology and synaptic loss. At 26 weeks of age, when both pathologies were clearly established, we observed severe brain atrophy in APP/PS1xdb/db animals as well as cortical thinning, accompanied by increased caspase activity. Reduced senile plaque burden and elevated soluble Aβ40 and 42 levels were observed in AD-T2D mice. Further assessment revealed a significant increase of neurite curvature in prediabetic-AD mice, and this effect was worsened in AD-T2D animals. Synaptic density loss, analyzed by array tomography, revealed a synergistic effect between T2D and AD, whereas an intermediate state was observed, once more, in prediabetic-AD mice. Altogether, our data suggest that early prediabetic hyperinsulinemia may exacerbate AD pathology, and that fully established T2D clearly worsens these effects. Therefore, it is feasible that early detection of prediabetic state and strict metabolic control could slow or delay progression of AD-associated neuropathological features.

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References

  1. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189

    Article  PubMed  PubMed Central  Google Scholar 

  2. Beeri MS, Haroutunian V, Schmeidler J, Sano M, Fam P, Kavanaugh A, Barr AM, Honer WG et al (2012) Synaptic protein deficits are associated with dementia irrespective of extreme old age. Neurobiol Aging 33(1125):e1121–1128

    Google Scholar 

  3. Robinson JL, Molina-Porcel L, Corrada MM, Raible K, Lee EB, Lee VM, Kawas CH, Trojanowski JQ (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer’s disease in the oldest-old. Brain 137:2578–2587

    Article  PubMed  PubMed Central  Google Scholar 

  4. Luchsinger JA, Tang MX, Shea S, Mayeux R (2004) Hyperinsulinemia and risk of Alzheimer disease. Neurology 63:1187–1192

    Article  PubMed  Google Scholar 

  5. Rundek T, Gardener H, Xu Q, Goldberg RB, Wright CB, Boden-Albala B, Disla N, Paik MC et al (2010) Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the northern Manhattan study. Arch Neurol 67:1195–1200

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MM (2010) Insulin metabolism and the risk of Alzheimer disease: the Rotterdam study. Neurology 75:1982–1987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61:661–666

    Article  PubMed  Google Scholar 

  8. Cheng G, Huang C, Deng H, Wang H (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 42:484–491

    Article  CAS  PubMed  Google Scholar 

  9. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R (2007) Relation of diabetes to mild cognitive impairment. Arch Neurol 64:570–575

    Article  PubMed  Google Scholar 

  10. Craft S (2009) The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 66:300–305

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. Faseb J 22:246–260

    Article  CAS  PubMed  Google Scholar 

  12. Hyman BT (2011) Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol 68:1062–1064

    Article  PubMed  Google Scholar 

  13. Eckman EA, Eckman CB (2005) Abeta-degrading enzymes: modulators of Alzheimer’s disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 33:1101–1105

    CAS  PubMed  Google Scholar 

  14. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE et al (2003) 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 U S A 100:4162–4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garcia-Alloza M (2014) Streptozotocin as a tool to induce central pathology and cognitive impairment in rodents. In: Gauthier EL (ed) Streptozotocin: uses, mechanism of action and side effects. Nova Science Publishers, Inc Hauppauge, NY

    Google Scholar 

  17. De Felice FG, Ferreira ST (2014) Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 63:2262–2272

    Article  PubMed  Google Scholar 

  18. Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, Masliah E (2008) Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res 86:3265–3274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramos-Rodriguez JJ, Jimenez-Palomares M, Murillo-Carretero MI, Infante-Garcia C, Berrocoso E, Hernandez-Pacho F, Lechuga-Sancho AM, Cozar-Castellano I et al (2015) Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer’s disease. Psychoneuroendocrinology 62:69–79

    Article  CAS  PubMed  Google Scholar 

  20. Ramos-Rodriguez JJ, Ortiz-Barajas O, Gamero-Carrasco C, de la Rosa PR, Infante-Garcia C, Zopeque-Garcia N, Lechuga-Sancho AM, Garcia-Alloza M (2014) Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice. Psychoneuroendocrinology 48C:123–135

    Article  Google Scholar 

  21. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M et al (2010) Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 107:7036–7041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR (2004) APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol Aging 25:885–892

    Article  CAS  PubMed  Google Scholar 

  23. Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM et al (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524

    Article  CAS  PubMed  Google Scholar 

  24. Ramos-Rodriguez JJ, Ortiz O, Jimenez-Palomares M, Kay KR, Berrocoso E, Murillo-Carretero MI, Perdomo G, Spires-Jones T, Cozar-Castellano I, Lechuga-Sancho AM, Garcia-Alloza M (2013) Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology

  25. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ et al (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A 106:4012–4017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press United States

  27. Ramos-Rodriguez JJ, Pacheco-Herrero M, Thyssen D, Murillo-Carretero MI, Berrocoso E, Spires-Jones TL, Bacskai BJ, Garcia-Alloza M (2013) Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in APP/PS1 mice. J Neuropathol Exp Neurol 72:272–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramos-Rodriguez JJ, Molina-Gil S, Rey-Brea R, Berrocoso E, Garcia-Alloza M (2013) Specific serotonergic denervation affects tau pathology and cognition without altering senile plaques deposition in APP/PS1 mice. PLoS One 8, e79947

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ramos-Rodriguez JJ, Infante-Garcia C, Galindo-Gonzalez L, Garcia-Molina Y, Lechuga-Sancho A, Garcia-Alloza M (2015) Increased spontaneous central bleeding and cognition impairment in APP/PS1 mice with poorly controlled diabetes mellitus. Mol Neurobiol

  30. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ (2007) Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 102:1095–1104

    Article  CAS  PubMed  Google Scholar 

  31. Ramos-Rodriguez JJ, Molina-Gil S, Ortiz-Barajas O, Jimenez-Palomares M, Perdomo G, Cozar-Castellano I, Lechuga-Sancho AM, Garcia-Alloza M (2014) Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models. PLoS One 9, e89229

    Article  PubMed  PubMed Central  Google Scholar 

  32. Maesako M, Uemura K, Iwata A, Kubota M, Watanabe K, Uemura M, Noda Y, Asada-Utsugi M et al (2013) Continuation of exercise is necessary to inhibit high fat diet-induced beta-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice. PLoS One 8, e72796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. D’Amore JD, Kajdasz ST, McLellan ME, Bacskai BJ, Stern EA, Hyman BT (2003) In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J Neuropathol Exp Neurol 62:137–145

    Article  PubMed  Google Scholar 

  34. Garcia-Alloza M, Dodwell SA, Meyer-Luehmann M, Hyman BT, Bacskai BJ (2006) Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J Neuropathol Exp Neurol 65:1082–1089

    Article  CAS  PubMed  Google Scholar 

  35. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jimenez-Palomares M, Ramos-Rodriguez JJ, Lopez-Acosta JF, Pacheco-Herrero M, Lechuga-Sancho AM, Perdomo G, Garcia-Alloza M, Cozar-Castellano I (2012) Increased Abeta production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab 11:1373–1380

    Article  Google Scholar 

  37. Perez SE, Dar S, Ikonomovic MD, DeKosky ST, Mufson EJ (2007) Cholinergic forebrain degeneration in the APPswe/PS1DeltaE9 transgenic mouse. Neurobiol Dis 28:3–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM (2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46:1604–1610

    Article  Google Scholar 

  39. Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, Munch G, Wood AG, Forbes J, Greenaway TM, Pearson S, Srikanth V (2013) Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care

  40. Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

    Article  CAS  PubMed  Google Scholar 

  41. Farr SA, Banks WA, Morley JE (2006) Effects of leptin on memory processing. Peptides 27:1420–1425

    Article  CAS  PubMed  Google Scholar 

  42. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T (2002) Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 113:607–615

    Article  CAS  PubMed  Google Scholar 

  43. Kim B, Feldman EL (2012) Insulin resistance in the nervous system. Trends Endocrinol Metab 23:133–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT (2004) Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci 24:4535–4540

    Article  CAS  PubMed  Google Scholar 

  45. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Infante-Garcia C, Ramos-Rodriguez JJ, Galindo-Gonzalez L, Garcia-Alloza M (2016) Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer’s disease and type 2 diabetes. Psychoneuroendocrinology 65:15–25

    Article  CAS  PubMed  Google Scholar 

  47. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Junta de Andalucia, Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo (P11-CTS-7847), Fundación Eugenio Rodríguez Pascual 2015, ISCIII–Subdirección General de Evaluación y Fomento de la Investigación and cofinanced by the European Union (Fondo Europeo de Desarrollo Regional, FEDER) “Una manera de hacer Europa” PI12/00675 (Monica Garcia-Alloza).

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Authors and Affiliations

  1. Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain

    Juan Jose Ramos-Rodriguez & Monica Garcia-Alloza

  2. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Tara Spires-Jones, Amy M. Pooler & Brian J. Bacskai

  3. Institute of Psychiatry, Psychology & Neuroscience, Department of Basic and Clinical Neuroscience, King’s College London, London, UK

    Amy M. Pooler

  4. Department of Pediatrics, School of Medicine, Universidad de Cadiz, Cadiz, Spain

    Alfonso Maria Lechuga-Sancho

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  1. Juan Jose Ramos-Rodriguez
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  6. Monica Garcia-Alloza
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Correspondence to Monica Garcia-Alloza.

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Ramos-Rodriguez, J.J., Spires-Jones, T., Pooler, A.M. et al. Progressive Neuronal Pathology and Synaptic Loss Induced by Prediabetes and Type 2 Diabetes in a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 54, 3428–3438 (2017). https://doi.org/10.1007/s12035-016-9921-3

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  • DOI: https://doi.org/10.1007/s12035-016-9921-3

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