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Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) can be treated with inhibitors of the enzyme acetylcholinesterase (AChE). Recent pre-clinical and clinical studies gave evidence that AChE-inhibitors have neuroprotective effects and thereby a disease-modifying potential. The mechanism of this action is still discussed. In an animal model oral administration of an AChE-inhibitor lead to an increase of brain derived neurotrophic factor (BDNF) in hippocampus and cortex. Recent studies have found a decrease of BDNF in the serum and brain of AD patients with potentially consecutive lack of neurotrophic support and contribution to progressive neurodegeneration. BDNF serum concentrations were assessed by ELISA in 19 AD patients and 20 age-matched healthy controls at baseline and in the AD patients after 15 months of treatment with donepezil 10 mg per day (one patient received just 5 mg). Before treatment with donepezil we found in AD significantly decreased BDNF serum concentrations (19.2 ± 3.7 ng/ml) as compared to healthy controls (23.2 ± 6.0 ng/ml, P = 0.015). After 15 months of treatment the BDNF serum concentration increased significantly in the AD patients (23.6 ± 7.0 ng/ml, P = 0.001) showing no more difference to the healthy controls (P = 0.882). The results of the present study confirm data of prior investigations that a down-regulation of BDNF in serum and brain of AD patients seems to begin with the first clinical symptoms and to be persistent. A treatment with the AChE-inhibitor donepezil is accompanied with an increase of BDNF serum concentration in AD patients reaching the level of healthy controls. Thus, up-regulation of BDNF might be part of a neuroprotective effect of AChE-inhibitors. The molecular mechanism of this potentially disease-modifying mechanism of action of donepezil should be clarified.

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References

  1. Akaike A (2006) Preclinical evidence of neuroprotection by cholinesterase inhibitors Alzheimer Dis Assoc Disord 20(2 Suppl 1):S8–S11

    Article  PubMed  CAS  Google Scholar 

  2. Bifrare YD, Kummer J, Joss P, Tauber MG, Leib SL (2005) Brain-derived neurotrophic factor protects against multiple forms of brain injury in bacterial meningitis. J Infect Dis 191(1):40–45

    Article  PubMed  CAS  Google Scholar 

  3. Blasko I, Grubeck-Loebenstein B (2003) Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer‘s disease. Drugs Aging 20(2):101–113

    Article  PubMed  CAS  Google Scholar 

  4. Brion JP, Anderton BH, Authelet M, Dayanandan R, Leroy K, Lovestone S, Octave JN, Pradier L, Touchet N, Tremp G (2001) Neurofibrillary tangles and tau phosphorylation. Biochem Soc Symp 67:81–88

    PubMed  CAS  Google Scholar 

  5. Diagnostic, statistical manual of mental disorders, 4th ed.: DSM-4. Washington DC: American Psychiatric Association, 1994

  6. Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/Macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16(8):2508–2521

    PubMed  CAS  Google Scholar 

  7. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-Mental-State”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  PubMed  CAS  Google Scholar 

  8. Foulstone EJ, Tavare JM, Gunn-Moore FJ (1999) Sustained phosphorylation and activation of protein kinase B correlates with brain-derived neurotrophic factor and insulin stimulated survival of cerebellar granule cells. Neurosci Lett 264(1–3):125–128

    Article  PubMed  CAS  Google Scholar 

  9. Francis PT, Nordberg A, Arnold SE (2005) A preclinical view of cholinesterase inhibitors in neuroprotection; do they provide more than symptomatic benefits in Alzheimer´s disease? Trends Pharmacol Sci 26(2):104–104

    Article  PubMed  CAS  Google Scholar 

  10. Fumagalli F, Racagni G, Riva MA (2006) The expanding role of BDNF: a therapeutic target for Alzheimer´s disease? Pharmacogenomics J 6(1):8−15

    Article  PubMed  CAS  Google Scholar 

  11. Gonul AS, Akdeniz F, Taneli F, Donat O, Eker Ç, Vahip S (2005) Effect of treatment on serum brain–derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 255(6):381–386

    Article  PubMed  Google Scholar 

  12. Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57(6):846–851

    Article  PubMed  CAS  Google Scholar 

  13. Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M (2000) Quantitation of BDNF mRNA in human parietal cortex by competetive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer‘s disease. Brain Res Mol Brain Res 76(2):347–354

    Article  PubMed  CAS  Google Scholar 

  14. Kaija H, Sami A, Martti H, Esa L, Riikka R; Kari M; Terho L (2007) Brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T are not associated with response to electroconvulsive therapy in major depressive disorder. Eur Arch Psychiatry Clin Neurosci. 257(1):31–35

    Article  PubMed  Google Scholar 

  15. Karege F, Schwald M, Cisse M (2002) Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 328(3):261–264

    Article  PubMed  CAS  Google Scholar 

  16. Kotani S, Yamauchi T, Teramoto T, Ogura H (2006) Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142:505–514

    Article  PubMed  CAS  Google Scholar 

  17. Laske C, Stransky E, Leyhe T, Eschweiler GW, Schott K, Langer H, Gawaz M (2006) Decreased brain-derived neurotrophic factor (BDNF)- and β-thromboglobulin (β-TG)- blood levels in Alzheimer’s disease. Thromb Haemost 113:1217–1224

    CAS  Google Scholar 

  18. Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A, Soekadar S, Richartz E, Koehler N, Bartels M, Buchkremer G, Schott K (2007) BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res 41:387–394

    Article  PubMed  Google Scholar 

  19. Lee TH, Kato H, Chen ST, Kogure K, Itoyama Y (2002) Expression disparity of brain-derived neurotrophic factor immunoreactivity and mRNA in ischemic hippocampal neurons. Neuroreport 13(17):2271–2275

    Article  PubMed  CAS  Google Scholar 

  20. Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjo BK, Persson H (1992) Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci USA 89:648–652

    Article  PubMed  CAS  Google Scholar 

  21. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC (2005) The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 26(1):115–123

    Article  PubMed  CAS  Google Scholar 

  22. Marmigere F, Choby C, Rage F, Richard S, Tapia-Arancibia L (2001) Rapid stimulatory effects of brain-derived neurotrophic factor and neurotrophin-3 on somatostatin release and intracellular calcium rise in primary hypothalamic cell cultures. Neuroendocrinology 74(1):43–54

    Article  PubMed  CAS  Google Scholar 

  23. Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594

    Article  PubMed  CAS  Google Scholar 

  24. Mc Khann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    CAS  Google Scholar 

  25. Michalski B, Fahnestock M (2003) Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Res Mol Brain Res 111(1–2):148–154

    Article  PubMed  CAS  Google Scholar 

  26. Mocchetti I, Bachis A (2004) Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death. Crit Rev Neurobiol 16(1–2):51–57

    Article  PubMed  CAS  Google Scholar 

  27. Nakajima K, Kikuchi Y, Ikoma E, Honda S, Ishikawa M, Liu Y, Kohsaka S (1998) Neurotrophins regulate the function of cultured microglia. Glia 24(3):272–289

    Article  PubMed  CAS  Google Scholar 

  28. Nordberg A (2006) Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord 20(2 Suppl 1): S12–S18

    Article  PubMed  CAS  Google Scholar 

  29. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ (1998) Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37(12):1553–1561

    Article  PubMed  CAS  Google Scholar 

  30. Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93:1412–1421

    Article  PubMed  CAS  Google Scholar 

  31. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7(5):695–702

    Article  PubMed  CAS  Google Scholar 

  32. Pliego RF, Bayatti N, Giannakoulopoulos X, Glover V, Bradford HF, Stern G, Sandler M (1997) Brain-derived neurotrophic factor in human platelets. Biochem Pharmacol 54:207–209

    Article  Google Scholar 

  33. Poduslo JF, Curran GL (1996) Permeability at the blood-brain barrier and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Mol Brain Res 36:280–286

    Article  PubMed  CAS  Google Scholar 

  34. Radka SF, Holst PA, Fritsche M, Altar CA (1996) Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res 709:122–301

    Article  PubMed  CAS  Google Scholar 

  35. Riepe MW (2005) Cholinergic treatment: what are the early neuropathological targets? Eur J Neurol 12(Suppl. 3):3–9

    Article  PubMed  Google Scholar 

  36. Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11(4):434–439

    Article  PubMed  CAS  Google Scholar 

  37. Villuendas G, Sanchez-Franco F, Palacios N, Fernandez M, Cacicedo L (2001) Involvement of VIP on BDNF-induced somatostatin gene expression in cultured fetal rat cerebral cortical cells. Brain Res Mol Brain Res 94(1–2):59–66

    Article  PubMed  CAS  Google Scholar 

  38. Winblad B, Jelic V (2004) Long-term treatment of Alzheimer disease: efficacy and safety of acetylcholinesterase inhibitors. Alzheimer Dis Assoc Disord 18(Suppl 1):S2–S8

    Article  PubMed  CAS  Google Scholar 

  39. World Health Organization (WHO) (1992) Tenth revision of the international classification of diseases. Chapter 5 (F): mental, behavioural disorders (including disorders of psychological development). Clinical Descriptions and Diagnosic Guidelines. WHO Geneva

    Google Scholar 

  40. Yamamoto H, Gurney ME (1990) Human platelets contain brain-derived neurotrophic factor. J Neurosci 10:3469–3478

    PubMed  CAS  Google Scholar 

  41. Yasutake C, Kuroda K, Yanagawa T, Okamura T, Yoneda H (2006) Serum BDNF, TNF-α, IL-1β levels in dementia patients. Eur Arch Psychiatry Clin Neurosci 256:402–406

    Article  PubMed  Google Scholar 

  42. Zhi-fei W, Li-li T, Han Y, Yu-jun W, Xi-can T (2006) Effects of huperzine A on memory deficits and neurotrophic factors production after transient cerebral ischemia and reperfusion in mice. Pharmacol Biochem Behav 83:603–611

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstraße 24, 72076, Tübingen, Germany

    T. Leyhe, Elke Stransky, G. W. Eschweiler, G. Buchkremer & C. Laske

  2. Geriatric Center at the University of Tübingen, Tübingen, Germany

    T. Leyhe & G. W. Eschweiler

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  1. T. Leyhe
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  2. Elke Stransky
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  3. G. W. Eschweiler
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  4. G. Buchkremer
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  5. C. Laske
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Correspondence to T. Leyhe.

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Leyhe, T., Stransky, E., Eschweiler, G.W. et al. Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosc 258, 124–128 (2008). https://doi.org/10.1007/s00406-007-0764-9

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  • DOI: https://doi.org/10.1007/s00406-007-0764-9

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