Abstract
During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) resulted into three drugs being registered for the first time in USA and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects are slowing cognitive deterioration and improving behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and direct 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 (AD) leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. In order to explain the long-term effect of ChEI, a mechanism based on ~amyloid metabolism, is postulated. Evidence for such an effect is available at experimental as well as at clinical level. Does cholinergic stabilization imply slowing down disability or delaying disease progression?
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References
Alvarez A (1997) Acetylcholinesterase promotes the aggregation of amyloid B-peptide fragments by forming a complex with the growing fibrils. J Mol Bioi 272: 348–361
Anand R, Hartman R, Messina J (1998) Long-term treatment with rivastigmine continue to provide benefits for up to one year. Fifth Int Geneva/Springfield Symposium on Advances in Alzheimer Therapy, Geneva, Abstracts, p 18
Bernhardt T, Woelk H (2000) Metrifonate demonstrates sustained improvement in cognition and global functioning in a 12-month, double blind placebo-controlled trial. Eur Neurol Soc Meeting, Jerusalem, p 36
FarlowM (2000) New approaches in asssessing delay of progression of AD. Symp Pivotal Research, World Alzheimer Congress, Washington D.C. Abstracts, pp 10–11
Giacobini E (1996) Cholinesterase inhibitors do more than inhibit cholinesterase. In: Becker R, Giacobini E (eds) Alzheimer disease: from molecular biology to therapy. Birkhiiuser, Boston, pp 187–204
Giacobini E (1998) Cholinesterase inhibitors for Alzheimer’s disease therapy, from tacrine to future applications. Neurochem Int 32: 413–419
Giacobini E (2000) Cholinesterase inhibitors: from the calabar bean to Alzheimetherapy. In: Giacobini E (ed) Cholinesterase and cholinesterase inhibitors. From molecular biology to therapy. Martin Dunitz, London, pp 181–22
Giacobini E (2001) Is anti-cholinesterase therapy of Alzheimer’s disease delaying progression? Aging Clin Exp Res 13: 247–254
Giacobini E, Gold G, Michel J-P (2001) Vaccination:traitement de demain pour lamaladie d’ Alzheimer? Med Hyg 59: 103–107
Haroutunian V, Wallace WC, Greig N (2000) Induction, secretion and pharmacological regulation of beta-APP in animal model systems. Sixth Int Stockholm/Springfield Symp, Adv in Alzheimer Therapy. Abstracts, p 81
Inestrosa N, Alvarez A, Perez CA (1996) Acetylcholinesterase accellerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16: 881–891
Inestrosa NC, Alvarez A, Reyes A, De Ferrari GV (2000) Acetylcholinesterase-amyloidpeptide interaction and Wnt signaling involvment in A-beta neurotoxicity. Acta Neurol Scand [Suppl 176]: 53–59
Lahiri DK, Farlow MR, Hintz N, Utsuki T, Greig NH (2000) Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer’s disease. Acta Neurol Scand [Suppl 176]:60–67
Matthews HP (2000) Donepezil in Alzheimer’s disease: eighteenmonth results from Southampton memory clinic. Int J Ger Psych 15: 713–720
Mori F, Lai CC, Fusi F, Giacobini E (1995) Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neurol Rep 6: 633–6
Nitsch RM (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258: 304–307
Pakaski M, Rakonczay Z, 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
Racchi M, Schmidt B, Koenig G (1999) Treatment with metrifonate promotes soluble amyloid precursor protein release from SH-SY5Y neuroblastoma cells. Alz Dis Assoc Disord 13: 679–688
Raskind MA, Peskind ER, Wessel T (2000) Galantamine in AD. A sixth month randomized, placebo-controlled trial with a 6-month extension. Neurology 54: 2261–2268
Rogers SL (2000) Long-term efficacy and safety of donezepil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharm 10: 195–203
Small DH, Sbema G, Li QX et al (1998) The beta-amyloid protein influences acetylcholinesterasye expression, assembly and glycosylation. 6th Int Conf Alzheimer’s Disease, Amsterdam. Abstracts
Suh Y-H, Chong Yh, Kim S-H et al (1996) Molecular physiology, biochemistry and pharmacology of Alzheimer’s amyloid precursor protein (APP). Ann NY Acad 786:169–183
Wallace WC, Bragin V, Robakis NK (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
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Giacobini, E. (2002). Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer’ disease. In: Jellinger, K.A., Schmidt, R., Windisch, M. (eds) Ageing and Dementia Current and Future Concepts. Journal of Neural Transmission. Supplementa, vol 62. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6139-5_17
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DOI: https://doi.org/10.1007/978-3-7091-6139-5_17
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