J Clin Neurol.  2011 Mar;7(1):10-18. 10.3988/jcn.2011.7.1.10.

A Common Pathogenic Mechanism Linking Type-2 Diabetes and Alzheimer's Disease: Evidence from Animal Models

Affiliations
  • 1Department of Neurology, Soonchunhyang University College of Medicine, Bucheon Hospital, Bucheon, Korea. sapark@schmc.ac.kr

Abstract

The failure of large-scale drug trials targeting the amyloidogenic pathway in Alzheimer's disease (AD) is increasing the need to identify a novel pathogenic mechanism. Studies finding a relationship between sporadic AD and type-2 diabetes mellitus (T2DM) are now receiving more attention. The risk for developing both T2DM and sporadic AD increases exponentially with age, and having T2DM doubles the risk of developing AD. The postmortem brains of AD patients show altered activities of insulin receptors and downstream molecules, as well as reduced protein and mRNA levels of insulin. More-recent laboratory research using animal models has identified mechanisms that are shared by diabetes and AD. Exogenous application of streptozotocin, which disrupts systemic insulin secretion, results in insulin deficiency, increased tau phosphorylation, and cognitive impairments that can be reversed by exogenous insulin supplementation. However, AD pathology is more severe in T2DM animal models exhibiting hyperinsulinemia and insulin resistance, and this is not modulated by insulin. The symptoms of this AD pathology included increased tau phosphorylation at multiple sites, increased tau cleavage, and greater neuronal and synaptic damage, even with increased amyloid beta protein production. It has therefore been suggested that hyperinsulinemia and insulin resistance represent major factors underlying AD in T2DM. A recent study involving cross-mating ob/ob and amyloid precursor protein transgenic mice provided evidence that T2DM and AD aggravate each other, and suggested that cerebral vessels constitute an important substrate that is commonly damaged by the two major disorders. Given the evidence provided by animal models, further investigation of the mechanisms underlying T2DM in AD should help to identify potential treatment targets in AD.

Keyword

Alzheimer's disease; animal model; diabetes; insulin resistance; mechanism

MeSH Terms

Alzheimer Disease
Amyloid
Amyloid beta-Peptides
Animals
Brain
Diabetes Mellitus
Humans
Hyperinsulinism
Insulin
Insulin Resistance
Mice
Mice, Transgenic
Models, Animal
Neurons
Phosphorylation
Receptor, Insulin
RNA, Messenger
Streptozocin
Amyloid
Amyloid beta-Peptides
Insulin
RNA, Messenger
Receptor, Insulin
Streptozocin

Reference

1. Suh GH, Knapp M, Kang CJ. The economic costs of dementia in Korea, 2002. Int J Geriatr Psychiatry. 2006. 21:722–728.
Article
2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002. 297:353–356.
Article
3. Rafii MS, Aisen PS. Recent developments in Alzheimer's disease therapeutics. BMC Med. 2009. 7:7.
Article
4. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 2010. 9:702–716.
Article
5. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997. 145:301–308.
Article
6. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999. 53:1937–1942.
Article
7. Grodstein F, Chen J, Wilson RS, Manson JE. Nurses' Health Study. Type 2 diabetes and cognitive function in community-dwelling elderly women. Diabetes Care. 2001. 24:1060–1065.
Article
8. Peila R, Rodriguez BL, Launer LJ. Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes. 2002. 51:1256–1262.
Article
9. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004. 61:661–666.
Article
10. Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology. 2004. 63:1181–1186.
Article
11. 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.
Article
12. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005. 8:247–268.
Article
13. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001. 50:537–546.
14. Kim B, Backus C, Oh S, Hayes JM, Feldman EL. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology. 2009. 150:5294–5301.
Article
15. Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007. 27:13635–13648.
Article
16. Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, et al. 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. 2008. 86:3265–3274.
Article
17. Brant AM, Jess TJ, Milligan G, Brown CM, Gould GW. Immunological analysis of glucose transporters expressed in different regions of the rat brain and central nervous system. Biochem Biophys Res Commun. 1993. 192:1297–1302.
Article
18. Salkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P. Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem. 2006. 96:1005–1015.
Article
19. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX. Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer's disease. Am J Pathol. 2009. 175:2089–2098.
Article
20. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005. 7:63–80.
Article
21. Li ZG, Zhang W, Sima AA. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes. 2007. 56:1817–1824.
Article
22. de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, et al. Caspase activation precedes and leads to tangles. Nature. 2010. 464:1201–1204.
Article
23. Janson J, Laedtke T, Parisi JE, O'Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004. 53:474–481.
Article
24. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004. 101:3100–3105.
Article
25. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003. 23:7084–7092.
Article
26. Killick R, Scales G, Leroy K, Causevic M, Hooper C, Irvine EE, et al. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem Biophys Res Commun. 2009. 386:257–262.
Article
27. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. 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. 2003. 100:4162–4167.
Article
28. Sudoh S, Frosch MP, Wolf BA. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and -insoluble pools in CHO-695 cells. Biochemistry. 2002. 41:1091–1099.
Article
29. Ke YD, Delerue F, Gladbach A, Götz J, Ittner LM. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. PLoS One. 2009. 4:e7917.
Article
30. Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis. 2010. 19:1205–1219.
Article
31. Plaschke K, Kopitz J, Siegelin M, Schliebs R, Salkovic-Petrisic M, Riederer P, et al. Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes in Tg2576 AbetaPP-overexpressing mice. J Alzheimers Dis. 2010. 19:691–704.
Article
32. Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004. 18:902–904.
Article
33. Kohjima M, Sun Y, Chan L. Increased food intake leads to obesity and insulin resistance in the tg2576 Alzheimer's disease mouse model. Endocrinology. 2010. 151:1532–1540.
Article
34. Julien C, Tremblay C, Phivilay A, Berthiaume L, Emond V, Julien P, et al. High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging. 2010. 31:1516–1531.
Article
35. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010. 107:7036–7041.
Article
36. Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, et al. Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse. Diabetologia. 2000. 43:932–938.
Article
37. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996. 382:685–691.
Article
38. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007. 282:33305–33312.
Article
39. Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell. 2009. 20:1533–1544.
40. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008. 22:246–260.
Article
41. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009. 106:1971–1976.
Article
42. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003. 423:435–439.
Article
43. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008. 104:1433–1439.
Article
44. Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001. 177:125–134.
Article
45. 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.
Article
46. Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology. 2003. 60:1899–1903.
Article
47. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003. 40:1087–1093.
Article
48. Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003. 162:313–319.
Article
49. Mistur R, Mosconi L, Santi SD, Guzman M, Li Y, Tsui W, et al. Current Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies. J Clin Neurol. 2009. 5:153–166.
Article
50. Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009. 132:1820–1832.
Article
51. Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995. 46:223–234.
Article
52. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, et al. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci U S A. 1994. 91:4766–4770.
Article
53. Necula M, Kuret J. Pseudophosphorylation and glycation of tau protein enhance but do not trigger fibrillization in vitro. J Biol Chem. 2004. 279:49694–49703.
Article
54. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005. 62:1539–1544.
55. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006. 12:1005–1015.
56. Desrocher M, Rovet J. Neurocognitive correlates of type 1 diabetes mellitus in childhood. Child Neuropsychol. 2004. 10:36–52.
Article
57. Lee ZS, Chan JC, Yeung VT, Chow CC, Lau MS, Ko GT, et al. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care. 1999. 22:1450–1457.
Article
58. Lupien S, Lecours AR, Lussier I, Schwartz G, Nair NP, Meaney MJ. Basal cortisol levels and cognitive deficits in human aging. J Neurosci. 1994. 14:2893–2903.
Article
59. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci. 2008. 11:309–317.
Article
60. Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry. 2006. 163:2164–2169.
Article
61. Huang CW, Lui CC, Chang WN, Lu CH, Wang YL, Chang CC. Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer's disease. J Clin Neurosci. 2009. 16:1283–1286.
Article
62. Schmidt R, Launer LJ, Nilsson LG, Pajak A, Sans S, Berger K, et al. Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes. 2004. 53:687–692.
63. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet. 1999. 354:919–920.
Article
Full Text Links
  • JCN
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr