Advertisement

Neurochemical Research

, Volume 28, Issue 3–4, pp 515–522 | Cite as

Cholinesterases: New Roles in Brain Function and in Alzheimer's Disease

  • Ezio Giacobini
Article

Abstract

The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission–experimental or pathological, such as in AD–leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on β-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.

Alzheimer's disease butyrylcholinesterase cholinesterase inhibitors cholinergic stabilization APP (amyloid precursor protein), β-amyloid. 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Farlow, M. 2000. New approaches in assessing delay of progression of AD. Symp. Pivotal Res. World Alzheimer Congress, Washington, D. C. Abstr:10–11.Google Scholar
  2. 2.
    Anand, R., Hartman, R., and Messina, J. 1998. Long-term treatment with rivastigmine continue to provide benefits for up to one year. Fifth International Geneva/Springfield Symposium on Advances in Alzheimer Therapy Geneva, Abstr.:18.Google Scholar
  3. 3.
    Nitsch, R. M. 1992. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307.PubMedGoogle Scholar
  4. 4.
    Mori, F., Lai, C. C., Fusi, F., and Giacobini, E. 1995. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neurol. Rep. 6:633–636.Google Scholar
  5. 5.
    Racchi, M., Schmidt, B., and Koenig, G. 1999. Treatment with metrifonate promotes soluble amyloid precursor protein release from SH-SY5Y neuroblastoma cells. Alz. Dis. Assoc. Dis 27: 679–688.Google Scholar
  6. 6.
    Pakaski, M., Rakonczay, Z., and Kasa, P. 2001. Reversible or irreversible cholinesterase inhibitors cause changes in neuronal amyloid percursor processing and protein kinase C level in vitro. Neurochem. Int. 38:219–226.PubMedGoogle Scholar
  7. 7.
    Giacobini, E. 1996. Cholinesterase inhibitors do more than inhibit cholinesterase. Pages 187–204, in Becker, R. and Giacobini, E. (eds.), Alzheimer Disease: From Molecular Biology to Therapy, Birkhäuser, Boston.Google Scholar
  8. 8.
    Nitsch, R. 2000. Muscarinic agonists reduce CSF levels of amy-loid beta-peptides in patients with Alzheimer's disease. XVth International Symposium of Medicinal Chemistry, Bologna, Abstr M1-41:52.Google Scholar
  9. 9.
    Lahiri, D. K., Farlow, M. R., Hintz, N., Utsuki, T., and Greig, N. H. 2000. Cholinesterase inhibitors, β-amyloid precursor protein and amyloid 3-peptides in Alzheimer's disease. Acta Neurol. Scand. (Suppl.) 176:60–67.Google Scholar
  10. 10.
    Svensson, A. L. and Giacobini, E. 2000. Cholinesterase inhibitors do more than inhibit cholinesterase. Pages 227–235, in Giacobini, E. (ed.), Cholinesterases and Cholinesterase Inhibitors, Martin Dunitz.Google Scholar
  11. 11.
    Shaw, K., Utsuki, T., Rogers, J., Qiang-Sheng, Y., Samba-murti, K., and Brossi, A. 2001. Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc. Natl. Acad. Sci. USA. 19:7605–7610.Google Scholar
  12. 12.
    Lahiri, D. K., Farlow, M. R., Ge, Y. W., Sambamurti, K., Utsuki, T., Ingram, D. K., and Greig, N. H. 2002. Phenserine: A new generation of cholinesterase inhibitors with amyloid-modifying properties. Seventh International Geneva Spring-field Symposium 2002. Abstr.:80.Google Scholar
  13. 13.
    Inestrosa, N. C., Alvarez, A., Reyes, A., and De Ferrari, G. V. 2000. Acetylcholinesterase-amyloid-peptide interaction and Wnt signaling involvment in A-beta neurotoxicity. Acta Neurol. Scand. (Suppl.) 176:53–59.Google Scholar
  14. 14.
    Inestrosa, N. C. and De Ferrari, G. V. Cholinesterase inhibitors with anti-amyloid properties. 7th International Geneva Springfield Symposium 2002. Abstr.:74.Google Scholar
  15. 15.
    Geula, C. and Mesulam, M. 1989. Special properties of cholinesterases in the cerebral cortex of Alzheimer's disease. Brain Res. 498:185–189.PubMedGoogle Scholar
  16. 16.
    Alvarez, A. 1997. Acetylcholinesterase promotes the aggregation of amyloid ∃-peptide fragments by forming a complex with the growing fibrils. J. Mol. Biol. 272:348–361.PubMedGoogle Scholar
  17. 17.
    De Ferrari, G. V., Canales, M. A., Shin, I., Weiner, L. M., Silman, I., and Inestrosa, N. C. 2001. A structural motif of acetylcholinesterase that promotes amyloid ∃-peptide fibril formation. Biochemistry 40:10447–10457.PubMedGoogle Scholar
  18. 18.
    Giacobini, E. 2000. Cholinesterase inhibitors: From the calabar bean to Alzheimer therapy. Pages 181–122, in Giacobini, E. (ed.), Cholinesterase and Cholinesterase Inhibitors: From Molecular Biology to Therapy, Martin Dunitz, London.Google Scholar
  19. 19.
    Saez-Valero, J., Sberna, G., McLean, C. A., and Small, D. H. 1999. Molecular isoform distribution and glycosylation of acetylcholinesterase are altered in brain and cerebrospinal fluid of patients with Alzheimer's disease. J. Neurochem. 72:1600–1608.PubMedGoogle Scholar
  20. 20.
    Small, D. H., Sberna, G., and Li, Q. X. 1998. The ∃-amyloid protein influence acetylcholinesterase expression, assembly and glycosylation. Sixth International Conference on Alzheimer's Disease and Related Disorders, Amsterdam. Abstr.:880.S.209.Google Scholar
  21. 21.
    Inestrosa, N., Alvarez, A., and Perez, C. A. 1996. Acetylcholinesterase accelerates assembly of amyloid-∃-peptides into Alzheimer's fibrils: Possible role of the peripheral site of the enzyme. Neuron 16:881–891.PubMedGoogle Scholar
  22. 22.
    Rees, T., Hammond, P., Younkin, S., Soreq, H., and Brimijoin, S., 2002. Acetyl-cholinesterase facilitates amyloid deposition in a mouse model of Alzheimer's disease. Seventh International Symposium Cholinergic Mechanisms, St. Moritz Abstr.:13.Google Scholar
  23. 23.
    Sberna, G., Saez-Valero, J., and Li, Q. X. 1998. Acetyl-cholinesterase is increased in the brains of transgenic mice expressing C-terminal fragment of the ∃-amyloid protein precursor of Alzheimer's disease. J. Neurochem. 71:723–731.PubMedGoogle Scholar
  24. 24.
    Haroutunian, V., Wallace, W. C., and Greig, N. 2000. Induction, secretion and pharmacological regulation of beta-APP in animal model systems. Sixth International Stockholm/Springfield Symposium Advances in Alzheimer Therapy. Abstr.:81.Google Scholar
  25. 25.
    Suh, Y. H., Chong, Y. H., and Kim, S. H. 1996. Molecular physiology, biochemistry and pharmacology of Alzheimer's amyloid precursor protein (APP). Ann. N. Y. Acad. Sci. 786:169–183.PubMedGoogle Scholar
  26. 26.
    Wallace, W. C., Bragin, V., and Robakis, N. K. 1991. Increased byosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis Meynert. Mol. Brain Res. 10:173–178.PubMedGoogle Scholar
  27. 27.
    Bernhardt, T. and Woelk, H. 2000. Metrifronate demonstrates sustained improvement in cognition and global functioning in a 12-month, double-blind placebo-controlled trial. Europ. Neurol. Soc. Meet. (Jerusalem), p. 36.Google Scholar
  28. 28.
    Winblad, B., Engedal, K., and Soininen, H. 1999. Donepezil enhances global function, cognition and activities of daily living compared with placebo one year. Twelfth Congretional ECNP, London. Abstr.:30.Google Scholar
  29. 29.
    Raskind, M. A., Peskind, E. R., and Wessel, T. 2000. Galanta-mine in AD: A sixth month randomized, placebo-controlled trial with a 6-month extension. Neurology 54:2261–2268.PubMedGoogle Scholar
  30. 30.
    Silver, A. 1974. The biology of cholinesterases. Elsev. Publ USA, Agricultural Res. Council Institute: 426–447.Google Scholar
  31. 31.
    Giacobini, E. 2001. Selective inhibitors of butyrylcholinesterase: A valid alternative for therapy of Alzheimer's disease? Drug Aging 18:891–898.Google Scholar
  32. 32.
    Wright, C. I, Geula, C., and Mesulam, M. M. 1993. Neuroglial cholinesterases in the normal brain and in Alzheimer's disease: Relationship to plaques, tangles and patterns of selective vulnerability. Ann. Neurol. 34:373–384.PubMedGoogle Scholar
  33. 33.
    Perry, E. K., Perry, R. H., Blessed G., and Tomlinson, B. E. 1978. Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol. Appl. Neurobiol. 4:273–277.PubMedGoogle Scholar
  34. 34.
    Cuadra, G., Summers, K., and Giacobini, E. 1994. Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo. J. Pharmacol. Exper. Ther. 270:277–284.Google Scholar
  35. 35.
    Giacobini, E., Griffini, P. L., Maggi T., et al. 1996. The effect of MF8622, a selective butyrylcholinesterase inhibitor on cortical levels of acetylcholine. Soc. Neurosci. 22:203.Google Scholar
  36. 36.
    Cuadra, G. and Giacobini E. 1995. Coadministration of cholinesterase inhibitors and idazoxan: Effects of neurotransmitters in rat cortex in vivo. J. Pharm. Exp. Ther. 273:230–240.Google Scholar
  37. 37.
    Greig, N. H., Utsuki, T., Yu, Q., et al. 2001. Butyryl-cholinesterase: A new therapeutic target in AD treatment? Alz. Insights 7,2, 1–4.Google Scholar
  38. 38.
    Mesulam, M. M., Guillozet, A., Shaw, P., Levey, A., Duysen, E. G., and Lockridge, O. 2002. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyl-cholinesterase to hydrolyse acetylocholine. Neuroscience 110: 627–639.PubMedGoogle Scholar
  39. 39.
    Mesulam, M. M. and Geula, C. 1994. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann. Neurol. 36:722–727.PubMedGoogle Scholar
  40. 40.
    Darvesh, S., MacKnight, C., and Rockwood, K. 2001. Butyryl-cholinesterase and cognitive function. Int. Psychogeriatr. 13: 461–464.PubMedGoogle Scholar
  41. 41.
    Costa, J., Anand, R., Cutler, N., et al. 1999. Correlation between cognitive effects and level of acetylcholinesterase inhibition in a trial of rivastigmine in Alzheimer's patients. Proc. Am. Psych. Assoc. Poster NR:561.Google Scholar
  42. 42.
    Giacobini, E., et al. 2002. Acetyl-and butyrylcholinesterase inhibition by rivastigmine in cerebrospinal fluid of patients with Alzheimer's disease correlates with cognitive benefit. J. Neural Transm. In press.Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Ezio Giacobini
    • 1
  1. 1.Department of Geriatrics, University of Geneva, Medical schoolUniversity Hospitals of GenevaThônex, GenevaSwitzerland

Personalised recommendations