Skip to main content
SpringerLink
Log in

What Protects Patients with Schizophrenia from Developing Alzheimer Pathology?

  • Chapter
  • First Online:
Brain Protection in Schizophrenia, Mood and Cognitive Disorders

Abstract

Disturbed insulin signal transduction and increased glycogen synthase kinase-3beta expression/activity are core features of Alzheimer’s disease (AD). Moreover, compromised insulin signalling (including reduced insulin-degrading enzyme activity) is blamed to significantly contribute to the development of typical hallmarks of AD: amyloid deposits and hyperphosphorylation of tau protein. Interestingly, patients with schizophrenia often suffer from the metabolic syndrome. Treatment with typical and atypical neuroleptics either initiates or further increases the metabolic problems of many schizophrenics. In post-mortem brains of schizophrenics considerable functional decrease of insulin receptors, disruption of the Akt-dependent insulin signalling system, and increased glycogen synthase kinase-3beta expression/activity have been found. The striking similarities of pathologic changes in brain insulin metabolism of schizophrenics and AD patients should lead to an increased incidence of AD in aged schizophrenics. Remarkably, this is not the case. We try to identify possible protective mechanisms that prevent AD pathology in patients with schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Abeta:

amyloid beta protein

AD:

Alzheimer’s disease

AGE:

advanced glycation end products

APP:

amyloid precursor protein

ATP:

Adenosine-5'-triphosphate

BACE1:

Beta-site amyloid precursor protein cleaving enzyme 1

Cat K:

cathepsin K CSF, cerebrospinal fluid

CNS:

central nervous system

DNA:

Deoxyribonucleic acid

GSK-3alpha/beta:

glycogen synthase kinase-3alpha/beta

IDE:

insulin-degrading enzyme

IGF-1:

Insulin-like growth factor-1

IR:

Insulin receptors

IRS:

insulin receptor substrate

MAPK:

mitogen-activated protein kinase

NFT:

neurofibrillary tangles

PDK:

phosphatidylinositol 3-kinase

PI3K:

phosphoinositide 3-kinase

SP:

senile plaques

sRAGE:

soluble receptor for advances glycation end products

Wnt:

Wingless (gene) and Int.

Amino acids: Ala:

alanine

Arg:

arginine

Asn:

asparagine

Asp:

aspartic acid

Glu:

glutamine

Gly:

glycine

His:

histidine

Ile:

isoleucine

Leu:

leucine

Lys:

lysine

Met:

methionine

Phe:

phenylalanine

Ser:

serine

Try:

tryptophan

Val:

valine

References

  1. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie 1907; 64:146–148

    Google Scholar 

  2. Bernstein HG. Proteases and Alzheimer’s disease: Present knowledge and emerging concepts of therapy. In: Lendeckel, U, Hooper, NM (eds) Proteases in the Brain. Springer, New York; 2005, pp. 1–23

    Chapter  Google Scholar 

  3. Chen M, Fernandez HL. Alzheimer movement re-examined 25 years later: is it a “disease” or a senile condition in medical nature? Front Biosci 2001; 6:E30–E40

    Article  PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm 2002; 109:991–1002

    Article  PubMed  CAS  Google Scholar 

  6. Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 2004; 490:115–125

    Article  PubMed  CAS  Google Scholar 

  7. Hebert LE, Scherr PA, Beckett LA, Albert MS, Pilgrim DM, Chown MJ, Funkenstein HH, Evans DA Age-specific incidence of Alzheimer’s disease in a community population. JAMA 1995; 273:1354–1359

    Article  PubMed  CAS  Google Scholar 

  8. Burns A, Iliffe S. Alzheimer’s disease. BMJ 2009; 338:b158

    Article  PubMed  Google Scholar 

  9. Thind K, Sabbagh MN. Pathological correlates of cognitive decline in Alzheimer’s disease. Panminerva Med 2007; 49:191–195

    PubMed  CAS  Google Scholar 

  10. Salkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 2007; (72):217–233

    Google Scholar 

  11. Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci USA 1978; 75:5737–5741

    Article  PubMed  CAS  Google Scholar 

  12. Dorn A, Bernstein HG, Rinne A, Ziegler M, Hahn HJ, Ansorge S. Insulin- and glucagonlike peptides in the brain. Anat Rec 1983; 207:69–77

    Article  PubMed  CAS  Google Scholar 

  13. Banks WA. The source of cerebral insulin. Eur J Pharmacol 2004; 490:5–12

    Article  PubMed  CAS  Google Scholar 

  14. Schwarzberg H, Bernstein HG, Reiser M, Günther O. Intracerebroventricular administration of insulin attenuates retrieval of a passive avoidance response in rats. Neuropeptides 1989; 13:79–81

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  16. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer A, Thalheimer A, Türk A, Hoyer S, Zöchling R, Boissl K W, Jellinger K, Riederer P. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 1998; 105:423–438

    Article  PubMed  Google Scholar 

  17. Frölich L, Blum-Degen D, Riederer P, Hoyer S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann NY Acad Sci 1999; 893:290–293

    Article  PubMed  Google Scholar 

  18. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte S. 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

    PubMed  CAS  Google Scholar 

  19. Neumann KF, Rojo L, Navarrete LP, Farias G, Reyes P, Maccioni RB. Insulin resistance and Alzheimer’s disease: molecular links & clinical implications. Curr Alzheimer Res 2008; 5:438–447

    Article  PubMed  CAS  Google Scholar 

  20. Zhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ, Frautschy SA, Cole GM. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci 2004; 24:11120–11126

    Article  PubMed  CAS  Google Scholar 

  21. Bernstein HG, Ansorge S, Riederer P, Reiser M, Frolich L, Bogerts B. Insulin-degrading enzyme in the Alzheimer’s disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 1999; 263:161–164

    Article  PubMed  CAS  Google Scholar 

  22. Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 2006; 27:190–198

    Article  PubMed  CAS  Google Scholar 

  23. Zhao Z, Xiang Z, Haroutunian V, Buxbaum JD, Stetka B, Pasinetti GM. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer’s disease. Neurobiol Aging 2007; 28:824–830

    Article  PubMed  CAS  Google Scholar 

  24. Janson J, Laedtke T, Parisi JE, O'Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004; 53:474–484

    Article  PubMed  CAS  Google Scholar 

  25. Götz J, Ittner LM, Lim YA. Common features between diabetes mellitus and Alzheimer’s disease. Cell Mol Life Sci 2009; 66:1321–1325

    Article  PubMed  CAS  Google Scholar 

  26. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta 2009; 1792:482–496

    Article  PubMed  CAS  Google Scholar 

  27. Beeri MS, Schmeidler J, Silverman, JM Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology 2008; 7:750–757

    Article  CAS  Google Scholar 

  28. Morel BA. Traité des maladies mentales. Masson, Paris; 1860

    Google Scholar 

  29. Kraepelin E. Psychiatrie. Ein Lehrbuch für Studirende und Aerzte. J. A. Barth, Leipzig; 1899

    Google Scholar 

  30. Kirkpatrick B, Messias E, Harvey PD, Fernandez-Egea E, Bowie CR. Is schizophrenia a syndrome of accelerated aging? Schizophr Bull 2008; 34:1024–1032

    Article  PubMed  Google Scholar 

  31. Friedman JI, Harvey PD, Coleman T, Moriarty PJ, Bowie C, Parrella M, White L, Adler D, Davis KL. Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alzheimer’s disease and normal aging. Am J Psychiatry 2001; 158:1441–1448

    Article  PubMed  CAS  Google Scholar 

  32. Sacks FM. Metabolic syndrome: epidemiology and consequences. J Clin Psychiatry, 2004; 65(Suppl 18):3–12

    PubMed  Google Scholar 

  33. Hagg S, Lindblom Y, Mjorndal T, Adolfsson R. High prevalence of the metabolic syndrome among a Swedish cohort of patients with schizophrenia. Int Clin Psychopharmacol 2006; 21:93–98

    Article  PubMed  Google Scholar 

  34. Casey DE. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med 2005; 118(Suppl 2): 15S–22S

    PubMed  Google Scholar 

  35. Holt RI, Peveler RC, Byrne CD. Schizophrenia, the metabolic syndrome and diabetes. Diabet Med 2004; 21:515–523

    Article  PubMed  CAS  Google Scholar 

  36. Zhao Z, Ksiezak-Reding H, Riggio S, Haroutunian V, Pasinetti GM. Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophr Res 2006; 84:1–14

    Article  PubMed  Google Scholar 

  37. De Hert M, Schreurs V, Sweers K, Van Eyck D, Hanssens L, Sinko S, Wampers M, Scheen A, Peuskens J, van Winkel R. Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res 2008; 101:295–303

    Article  PubMed  Google Scholar 

  38. Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004; 66:51–57

    Article  PubMed  Google Scholar 

  39. Perez-Iglesias R, Mata I, Pelayo-Teran JM, Amado JA, Garcia-Unzueta MT, Berja A, Martinez-Garcia O, Velasquez-Barquero JL, Crespo-Facorro, B. Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naive population. Schizophr Res 2006; 107:115–121

    Article  Google Scholar 

  40. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry 2004; (Suppl 47):S64–S66

    Google Scholar 

  41. Thakore JH, Mann JN, Vlahos I, Martin A, Reznek R. Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia. Int J Obes Relat Metab Disord 2002; 26:137–141

    Article  PubMed  CAS  Google Scholar 

  42. Thakore JH. Metabolic syndrome and schizophrenia. Br J Psychiatry 2005; 186:455–456

    Article  PubMed  Google Scholar 

  43. Huang JT, Leweke FM, Oxley D, Wang L, Harris N, Koethe D, Gerth CW, Nolden BM, Gross S, Schreiber D, Reed B, Bahn S. Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med 2006; 3: e428

    Article  PubMed  CAS  Google Scholar 

  44. Wang HC, Yang YK, Chen PS, Lee IH, Yeh TL, Lu RB. Increased plasma leptin in antipsychotic-naive females with schizophrenia, but not in males. Neuropsychobiology 2007; 56:213–215

    Article  PubMed  CAS  Google Scholar 

  45. Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia A, Esmatjes E, Garcia-Rizo C, Kirkpatrick B. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br J Psychiatry 2009; 194:434–438

    Article  PubMed  Google Scholar 

  46. Mitchell BD. Clustering of schizophrenia with other comorbidities – what can we learn? Schizophr Bull 2009; 35:282–283

    Article  PubMed  Google Scholar 

  47. Mukherjee S, Schnur DB, Reddy R. Family history of type 2 diabetes in schizophrenic patients. Lancet 1989; 1(8636):495

    Article  PubMed  CAS  Google Scholar 

  48. Adams PF, Marano MA. Current estimates from the National Health Interview Survey, 1994. Vital Health Stat 1995; 10(193 Pt 1):1–260

    Google Scholar 

  49. Bernstein HG, Ernst T, Lendeckel U, Bukowska A, Ansorge A, Stauch R, ten Have ST, Steiner J, Dobrowolny H, Bogerts B. Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia. J Psychiatr Res 2009; 43: 1095–1105.

    Google Scholar 

  50. Henderson DC, Cagliero E, Copeland PM, Borba CP, Boxill R, Freudenreich U, Cather C, Eden Evins A, Goff DC. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 2005; 62:19–28

    Article  PubMed  CAS  Google Scholar 

  51. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 1992; 49:522–530

    Article  PubMed  CAS  Google Scholar 

  52. Sharma MD, Garber AJ, Farmer JA. Role of insulin signaling in maintaining energy homeostasis. Endocr Pract 2008; 14:373–380

    PubMed  Google Scholar 

  53. Chang CK, Ulrich CM. Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia 2003; 46:595–607

    Article  PubMed  CAS  Google Scholar 

  54. Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 1998; 335(Pt 1):1–13

    Google Scholar 

  55. Zhang X, Zhang S, Yamane H, Wahl R, Ali A, Lofgren JA, Kendall RL. Kinetic mechanism of AKT/PKB enzyme family. J Biol Chem 2006; 281:13949–13956

    Article  PubMed  CAS  Google Scholar 

  56. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004; 36:131–137

    Article  PubMed  CAS  Google Scholar 

  57. Koros E, Dorner-Ciossek C. The role of glycogen synthase kinase-3beta in schizophrenia. Drug News Perspect 2007; 20:437–445

    Article  PubMed  CAS  Google Scholar 

  58. Altar CA, Hunt RA, Jurata LW, Webster MJ, Derby E, Gallagher P, Lemire A, Brockman J, Laeng P. Insulin, IGF-1, and muscarinic agonists modulate schizophreni associated genes in human neuroblastoma cells. Biol Psychiatry 2008; 64:1077–1087

    Article  PubMed  CAS  Google Scholar 

  59. Huang JT, Leweke FM, Tsang TM, Koethe D, Kranaster L, Gerth CW, Gross S, Schreiber D, Ruhrmann S, Schultze-Lutter F, Klosterkötter J, Holmes E, Bahn S. CSF metabolic and proteomic profiles in patients prodromal for psychosis. PLoS ONE 2007; 2:e756

    Google Scholar 

  60. White KE, Cummings JL. Schizophrenia and Alzheimer’s disease: clinical and pathophysiologic analogies. Compr Psychiatry 1996; 37:188–195

    Article  PubMed  CAS  Google Scholar 

  61. Broadway J, Mintzer J. The many faces of psychosis in the elderly. Curr Opin Psychiatry 2007; 20:551–558

    Article  PubMed  Google Scholar 

  62. Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res 1999; 40:87–99

    Article  PubMed  CAS  Google Scholar 

  63. Byerly MJ, Weber MT, Brooks DL, Snow LR, Worley MA, Lescouflair E. Antipsychotic medications and the elderly: effects on cognition and implications for use. Drugs Aging 2001; 18:45–61

    Article  PubMed  CAS  Google Scholar 

  64. Baldessarini RJ, Hegarty JD, Bird ED, Benes FM. Meta-analysis of postmortem studies of Alzheimer’s disease-like neuropathology in schizophrenia. Am J Psychiatry 1997; 154:861–863

    PubMed  CAS  Google Scholar 

  65. Niizato K, Arai T, Kuroki N, Kase K, Iritani S, Ikeda K. Autopsy study of Alzheimer’s disease brain pathology in schizophrenia. Schizophr Res 1998; 3:177–184

    Article  Google Scholar 

  66. Murphy GM, Jr., Lim KO, Wieneke M,Ellis WG, Forno LS, Hoff AL, Nordahl T. No neuropathologic evidence for an increased frequency of Alzheimer’s disease among elderly schizophrenics. Biol Psychiatry 1998; 43:205–209

    Article  PubMed  Google Scholar 

  67. Purohit DP, Perl DP, Haroutunian V, Powchik P, Davidson M, Davis KL. Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998; 55:205–211

    Article  PubMed  CAS  Google Scholar 

  68. Dwork AJ, Susser ES, Keilp J ,Waniek C, Liu D, Kaufman M, Zemishlany Z, Prohovnik I. Senile degeneration and cognitive impairment in chronic schizophrenia. Am J Psychiatry 1998; 155:1536–1543

    PubMed  CAS  Google Scholar 

  69. Bozikas VP, Kovari E, Bouras C, Karavatos A. Neurofibrillary tangles in elderly patients with late onset schizophrenia. Neurosci Lett 2002; 324:109–112

    Article  PubMed  CAS  Google Scholar 

  70. Religa D, Laudon H, Styczynska M, Winblad B, Naslund J, Haroutunian V. Amyloid beta pathology in Alzheimer’s disease and schizophrenia. Am J Psychiatry 2003; 160:867–872

    Article  PubMed  Google Scholar 

  71. Nelson PT, Abner EL, Scheff SW, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Patel E, Merkesbery WR. Alzheimer’s-type neuropathology in the precuneus is not increased relative to other areas of neocortex across a range of cognitive impairment. Neurosci Lett 2009; 450:336–339

    Article  PubMed  CAS  Google Scholar 

  72. Zach P, Kristofikova Z, Mrzilkova J Majer E, Selinger P, Spaniel F, Ripova D, Kenney J. Planum temporale analysis via a new volumetric method in autoptic brains of demented and psychotic patients. Curr Alzheimer Res 2009; 6:69–76

    Article  PubMed  CAS  Google Scholar 

  73. Nishioka N, Arnold SE. Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry 2004; 12:167–175

    PubMed  Google Scholar 

  74. Katsel P, Davis KL, Li C Tan W, Greenstein E, Kleiner Hoffmann LB, Haroutunian V. Abnormal indices of cell cycle activity in schizophrenia and their potential association with oligodendrocytes. Neuropsychopharmacology 2008; 33:2993–3009

    Article  PubMed  CAS  Google Scholar 

  75. Raedler TJ, Wiedemann K. CSF-studies in neuropsychiatric disorders. Neuro Endocrinol Lett 2006 27:297–305

    PubMed  CAS  Google Scholar 

  76. Arnold SE. Contributions of neuropathology to understanding schizophrenia in late life. Harv Rev Psychiatry 2001; 9:69–76

    Article  PubMed  CAS  Google Scholar 

  77. Leger JM, Moulias R, Robert P, Vellas B, Chapuy PH, Monfort JC, Khoshnood B, Bouee S, Rebah N, Gerard D. Agitation and aggressiveness among the elderly population living in nursing or retirement homes in France. Int Psychogeriatr 2002; 14:405–416

    Article  PubMed  Google Scholar 

  78. Harrison BE, Therrien B. Effect of antipsychotic medication use on memory in patients with Alzheimer’s disease: Assessing the potential risk for accelerated recent autobiographical memory loss. J Gerontol Nurs 2007; 33:11–20

    PubMed  Google Scholar 

  79. Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu LM, Jacoby R. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009; 8:151–157

    Article  PubMed  CAS  Google Scholar 

  80. Higaki J, Murphy GM, Jr., Cordell B. Inhibition of beta-amyloid formation by haloperidol: a possible mechanism for reduced frequency of Alzheimer’s disease pathology in schizophrenia. J Neurochem 1997; 68:333–336

    Article  PubMed  CAS  Google Scholar 

  81. Palotas A, Penke B, Palotas M, Kenderessy AS, Kemeny L, Kis E, Vincze G, Janka Z, Kalman J. Haloperidol attenuates beta-amyloid-induced calcium imbalance in human fibroblasts. Skin Pharmacol Physiol 2004; 17:195–199

    Article  PubMed  CAS  Google Scholar 

  82. Xu H, Wang H, Zhuang L, Yan B, Yu Y, Wei Z, Zhang Y, Dyck LE, Richardson SJ, He J, Li X, Kong J, Li XM. Demonstration of an anti-oxidative stress mechanism of quetiapine: implications for the treatment of Alzheimer’s disease. FEBS J 2008; 275:3718–3728

    Article  PubMed  CAS  Google Scholar 

  83. Ballard CG, Perry RH, McKeith IG, Perry EK. Neuroleptics are associated with more severe tangle pathology in dementia with Lewy bodies. Int J Geriatr Psychiatry 2005; 20:872–875

    Article  PubMed  CAS  Google Scholar 

  84. Mobascher A, Winterer G. The molecular and cellular neurobiology of nicotine abuse in schizophrenia. Pharmacopsychiatry 2008; 41(Suppl 1):S51–S59

    Article  PubMed  CAS  Google Scholar 

  85. Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, Breslau N, Brown RA, George TP, Williams J, Calhoun PS, Riley WT. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 2008; 10:1691–1715

    Article  PubMed  Google Scholar 

  86. Gierke P, Zhao C, Bernstein HG, Noack C, Anand R, Heinemann U, Braunewell KH. Implication of neuronal Ca2+ -sensor protein VILIP-1 in the glutamate hypothesis of schizophrenia. Neurobiol Dis 2008; 32:162–175

    Article  PubMed  CAS  Google Scholar 

  87. Court JA, Johnson M, Religa D, Keverne J, Kalaria R, Jaros E, Mckeith IG, Perry RH, Naslund J, Perry EK et al. Attenuation of Abeta deposition in the entorhinal cortex of normal elderly individuals associated with tobacco smoking. Neuropathol Appl Neurobiol 2005; 31:522–535

    Article  PubMed  CAS  Google Scholar 

  88. Vilkov GA, Martirosian VV, Trapezontseva RA, Kozlova LS, Ellanskii I. The kinin and plasmin systems of the blood serum and cerebro- spinal fluid in patients with multiple sclerosis and schizophrenia. Zh Nevropatol Psikhiatr Im S S Korsakova 1989; 89:23–27

    PubMed  CAS  Google Scholar 

  89. Dean B, Soulby A, Evin GM, Scarr E. Levels of [(3)H]pirenzepine binding in Brodmann’s area 6 from subjects with schizophrenia is not associated with changes in the transcription factor SP1 or BACE1. Schizophr Res 2008; 106:229–236

    Article  PubMed  Google Scholar 

  90. Tomita T. Secretase inhibitors and modulators for Alzheimer’s disease treatment. Expert Rev Neurother 2009; 9:661–679

    Article  PubMed  CAS  Google Scholar 

  91. Boonen RA, van Tijn P, Zivkovic D. Wnt signaling in Alzheimer’s disease: up or down, that is the question. Ageing Res Rev 2009; 8:71–82

    Article  PubMed  CAS  Google Scholar 

  92. Zhang J, Chen J, Xu Q, Shen Y. Does the presenilin 2 gene predispose to schizophrenia? Schizophr Res 2009; 109:121–129

    Article  PubMed  Google Scholar 

  93. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 2008; 104:1433–1439

    Article  PubMed  CAS  Google Scholar 

  94. Hernandez F, Avila J. The role of glycogen synthase kinase 3 in the early stages of Alzheimer’s disease. FEBS Lett 2008; 582:3848–3854

    Article  PubMed  CAS  Google Scholar 

  95. Kwok JB, Loy CT, Hamilton G, Lau E, Hallup M, Williams J, Owen MJ, Broe GA, Tang N, Lam L, Powell JF. Glycogen synthase kinase-3beta and tau genes interact in Alzheimer’s disease. Ann Neurol 2008; 64:446–454

    Article  PubMed  CAS  Google Scholar 

  96. Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA . GSK3 inhibitors show benefits in an Alzheimer’s disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiol Dis 2009; 33:193–206

    Article  PubMed  CAS  Google Scholar 

  97. Martinez A, Perez DI. GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer’s disease? J Alzheimers Dis 2008; 15:181–191

    PubMed  CAS  Google Scholar 

  98. Cotter D, Kerwin R, al-Sarraji S, Brion JP, Chadwich A, Lovestone A, Anderton B, Everall I. Abnormalities of Wnt signalling in schizophrenia––evidence for neurodevelopmental abnormality. Neuroreport 1998; 9:1379–1383

    Article  PubMed  CAS  Google Scholar 

  99. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 2000; 157:831–833

    Article  PubMed  CAS  Google Scholar 

  100. Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton, B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 2001; 302:117–120

    Article  PubMed  CAS  Google Scholar 

  101. Nadri C, Dean B, Scarr E, Agam G. GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. Schizophr Res 2004; 71(2–3):377–382

    Article  PubMed  Google Scholar 

  102. Roh MS, Seo MS, Kim Y, Kim SH, Jeon WJ, Ahn YM, Kang UG, Juhnn YS, Kim YS. Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex. Exp Mol Med 2007; 39:353–360

    Article  PubMed  CAS  Google Scholar 

  103. Beaulieu JM, Gainetdinov RR, Caron MG. Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 2009; 49:327–347

    Article  PubMed  CAS  Google Scholar 

  104. Souza RP, Romano-Silva MA, Lieberman JA, Meltzer HY, Wong AH, Kennedy JL. Association study of GSK3 gene polymorphisms with schizophrenia and clozapine response. Psychopharmacology (Berl) 2008; 200(2):177–186

    Article  CAS  Google Scholar 

  105. Keri S, Seres I, Kelemen O, Benedek G. Neuregulin 1-stimulated phosphorylation of AKT in psychotic disorders and its relationship with neurocognitive functions. Neurochem Int 2009; doi: 10.1016/j neuint 2009.06.002

    Google Scholar 

  106. De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene 2006; 25:7545–7553

    Article  PubMed  CAS  Google Scholar 

  107. Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 2007; 30:142–149

    Article  PubMed  CAS  Google Scholar 

  108. Ko F, Tallerico T, Seeman P. Antipsychotic pathway genes with expression altered in opposite direction by antipsychotics and amphetamine. Synapse 2006; 60:141–151

    Article  PubMed  CAS  Google Scholar 

  109. Bernstein HG, Bukowska A, Dobrowolny H, Bogerts B, Lendeckel U. Cathepsin K and schizophrenia. Synapse 2007; 61:252–253

    Article  PubMed  CAS  Google Scholar 

  110. Bernstein HG, Bogerts B, Lendeckel U. Cathepsin K and metabolic abnormalities in schizophrenia. Arterioscler Thromb Vasc Biol 2008; 28: e163

    Article  PubMed  CAS  Google Scholar 

  111. Lendeckel U, Kahne T, Ten Have S, Bukowska A, Wolke C, Bogerts B, Keilhoff G, Bernstein H-G. Cathepsin K generates enkephalin from beta-endorphin: a new mechanism with possible relevance for schizophrenia. Neurochem Int 2009; 54:410–417

    Article  PubMed  CAS  Google Scholar 

  112. Bohne S, Sletten K, Menard R, Bühling F, Vöckler S, Wrenger E, Roessner A, Röcken C. Cleavage of AL amyloid proteins and AL amyloid deposits by cathepsins B, K, and L. J Pathol 2004; 203:528–537

    Article  PubMed  CAS  Google Scholar 

  113. Rocken C, Fandrich M, Stix B, Tannert A, Hortschansky P, Reindeckel T, Saftig P, Kähne T, Menard R, Ancsin JB, Bühling F. Cathepsin protease activity modulates amyloid load in extracerebral amyloidosis. J Pathol 2006; 210:478–487

    Article  PubMed  CAS  Google Scholar 

  114. Schlenzig D, Manhart S, Cinar Y Kleinschmidt M, Hause G, Willbold D, Funke SA, Schilling S, Demuth HU. Pyroglutamate Formation Influences Solubility and amyloidogenicity of amyloid peptides. Biochemistry 2009; doi: 10.1021/bi900818a

    Google Scholar 

  115. Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla M, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat Med 2008; 14:1106–1111

    Article  PubMed  CAS  Google Scholar 

  116. Hou WS, Li Z, Buttner FH, Bartnik E, Brömme D. Cleavage site specificity of cathepsin K toward cartilage proteoglycans and protease complex formation. Biol Chem 2003; 384:891–897

    Article  PubMed  CAS  Google Scholar 

  117. Farber NB, Newcomer JW, Olney JW. The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer’s disease. Prog Brain Res 1998; 116:421–437

    CAS  Google Scholar 

  118. Edgar PF, Schonberger SJ, Dean B, Faull RL, Kydd R, Cooper GJ. A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer’s disease individuals. Mol Psychiatry 1999; 4:173–178

    Article  PubMed  CAS  Google Scholar 

  119. Go RC, Perry RT, Wiener H, Bassett SS, Blacker D, Devlin B, Sweet RA. Neuregulin-1 polymorphism in late onset Alzheimer’s disease families with psychoses. Am J Med Genet B Neuropsychiatr Genet 2005; 139B(1):28–32

    Article  PubMed  CAS  Google Scholar 

  120. Bertram I, Bernstein HG, Lendeckel U, Bukowska A, Dobrowolny H, Keilhoff G, Kanakis D, Mawrin C, Bielau H, Falkai P, Bogerts B. Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. Ann NY Acad Sci 2007; 1096:147–156

    Article  PubMed  CAS  Google Scholar 

  121. Ueberham U, Arendt T. The expression of cell cycle proteins in neurons and its relevance for Alzheimer’s disease. Curr Drug Targets CNS Neurol Disord 2005; 4:293–306

    Article  PubMed  CAS  Google Scholar 

  122. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006; 11:514–522

    Article  PubMed  CAS  Google Scholar 

  123. Morgan D. Amyloid, memory and neurogenesis. Exp Neurol 2007; 205:330–335

    Article  PubMed  CAS  Google Scholar 

  124. Schulte-Herbruggen O, Jockers-Scherubl MC, Hellweg R. Neurotrophins: from pathophysiology to treatment in Alzheimer’s disease. Curr Alzheimer Res 2008; 5:38–44

    Article  PubMed  Google Scholar 

  125. Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A. Astroglia in dementia and Alzheimer’s disease. Cell Death Differ 2009; 16:378–385

    Article  PubMed  CAS  Google Scholar 

  126. Stricker NH, Schweinsburg BC, Delano-Wood L, Wierenga CE, Bangen KJ, Haaland KY, Frank LR, Salmon DP, Bondi MW. Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer’s disease supports retrogenesis. Neuroimage 2009; 45:10–16

    Article  PubMed  CAS  Google Scholar 

  127. Li L, Holscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 2007; 56:384–402

    Article  PubMed  CAS  Google Scholar 

  128. Steiner J, Walter M, Wunderlich MT, Bernstein HG, Panteli B, Brauner M, Jacobs R, Gos T, Rothermundt M, Bogerts B. A New Pathophysiological Aspect of S100B in Schizophrenia: Potential Regulation of S100B by Its Scavenger Soluble RAGE. Biol Psychiatry 2009; 65:1107–1110

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Magdeburg, Magdeburg, Germany

    Hans-Gert Bernstein, Theresia S. Ernst Ph.D. (Student, Associate Professor), Henrik Dobrowolny M.S. (Electronics Engineer), Johann Steiner M.S. (Senior physician) & Bernhard Bogerts M.D. (Professor)

  2. Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany

    Uwe Lendeckel Ph.D. (Professor)

Authors
  1. Hans-Gert Bernstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theresia S. Ernst Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uwe Lendeckel Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henrik Dobrowolny M.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johann Steiner M.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernhard Bogerts M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Gert Bernstein .

Editor information

Editors and Affiliations

  1. Sha'ar Menashe Mental Health Center, Hadera, 38814, Israel

    Michael S. Ritsner

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Bernstein, HG., Ernst, T.S., Lendeckel, U., Dobrowolny, H., Steiner, J., Bogerts, B. (2010). What Protects Patients with Schizophrenia from Developing Alzheimer Pathology?. In: Ritsner, M. (eds) Brain Protection in Schizophrenia, Mood and Cognitive Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8553-5_3

Download citation

Publish with us

Policies and ethics

Search

Navigation