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Cultured Cells as a Screen for Novel Treatments of Alzheimer's Disease

Cultured Cells as a Screen for Novel Treatments of Alzheimer's Disease Abstract • Two easily measured abnormal properties of fibroblasts from patients with Alzheimer's disease have been utilized to develop an in vitro test system for screening novel therapeutic agents for Alzheimer's disease. The abnormal properties selected for study were increased isoproterenol-stimulated cyclic adenosine monophosphate production and decreased pH (measured by the weak-acid distribution method). L-Carnitine was tested as a potential therapeutic agent, since it has been used to treat a variety of experimental metabolic encephalopathies. The addition of L-carnitine normalized both of these properties in the Alzheimer cells. Tissue culture may aid as a preliminary screen for identifying novel approaches to the treatment of Alzheimer's disease. References 1. Summers WK, Majovski LK, Marsh GM, Tachiki K, Kling A. Oral tetrahydroacridine in long term treatment of senile dementia Alzheimer type . N Engl J Med . 1986;315:1241-1245.Crossref 2. Ames BN. Dietary carcinogens and anticarcinogens . Science . 1983;221:1256-1264.Crossref 3. Baker AC, Ko L-W, Blass JP. Systemic manifestations of Alzheimer's disease . Age . 1988;11:60-65.Crossref 4. Johnson WG. The clinical spectrum of hexosaminidase deficiency diseases . Neurology . 1981;31:1453-1456.Crossref 5. Pettegrew JW, Nichols JS, Stewart RM. Fluorescence spectroscopy on Huntington's fibroblasts . J Neurochem . 1979;33:905-911.Crossref 6. Malow BA, Baker AC, Gleason PM, Blass JP. Carnitine in Alzheimer's disease fibroblasts and patients . Clin Res . 1987;35:579A. 7. L'Allemain G, Paris S, Poyssegur J. Growth factor action and intracellular pH regulation in fibroblasts . J Biol Chem . 1984;259:5809-5815. 8. McSwigan JD. Alzheimer's disease fibroblasts accumulate more cyclic AMP in response to β-adrenergic stimulation vs normal fibroblasts . Neurosci Abstr . 1986;12:1316. 9. Hanson DR, Sheppard JR. Hormone responsiveness in cultured human skin fibroblasts from individuals with Down syndrome and Alzheimer disease . Am J Hum Genet . 1979;31:49A. 10. Sims NR, Finegan JM, Blass JP, Bowen DM, Neary D. Mitochondrial function in brain tissue in primary degenerative dementia . Brain Res . 1987;436:30-38.Crossref 11. Sims NR, Finegan JM, Blass JP. Altered metabolic properties of cultured skin fibroblasts in Alzheimer's disease . Ann Neurol . 1987;21:451-457.Crossref 12. Peterson C, Ratan RR, Shelanski ML, Goldman JE. Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors . Proc Natl Acad Sci USA . 1986;83:7999-8001.Crossref 13. Rebouche CJ, Engel AG. Carnitine metabolism and deficiency syndromes . Mayo Clin Proc . 1983;58:533-540. 14. Seccombe DW, Snyder F, Parsons HG. L-Carnitine for methylmalonic aciduria . Lancet . 1982;2:1401.Crossref 15. Stumpf DA, Parker WD, Angeline C. Carnitine deficiency, organic acidemias, and Reye's syndrome . Neurology . 1985;35:1041-1045.Crossref 16. Coulter DL. Carnitine deficiency: a possible mechanism for valproate toxicity . Lancet . 1984;1:689.Crossref 17. Shug AL, Hayes B, Huth PJ, et al. Changes in carnitine-linked metabolism during ischemia, thermal injury, and shock . In: Frenkel RA, McGarry JD, eds. Carnitine Biosynthesis, Metabolism, and Functions . Orlando, Fla: Academic Press Inc, 1980:321-340. 18. Kim CS, Dorgan DR, Roe CR. L-Carnitine: therapeutic strategy for metabolic encephalopathy . Brain Res . 1984;310:149-153.Crossref 19. Costell M, Miguez MP, O'Connor JE, Grisdea S. Effect of hyperammonemia on the levels of carnitine in mice . Neurology . 1987;37:804-808.Crossref 20. Folts JD, Shug AL, Koke JR, Bittar N. Protection of the ischemic dog myocardium with carnitine . Am J Cardiol . 1978;41:1209-1214.Crossref 21. Peterson C, Goldman JE. Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors . Proc Natl Acad Sci USA . 1986;83:2758-2762.Crossref 22. Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain . Int J Clin Pharm Ther Toxicol . 1986;24:511-516. 23. Bremer J. Carnitine: metabolism and functions . Physiol Rev . 1983;63:1420-1480. 24. Dolezal V, Tucek S. Utilization of citrate, acetylcarnitine, acetate, pyruvate, and glucose for the synthesis of acetylcholine in rat brain slices . J Neurochem . 1981;36:1323-1330.Crossref 25. Blum K, Seifter E, Seifter J. The pharmacology of d- and l-carnitine: comparison with choline and acetylcholine . J Pharmacol Exp Ther . 1971;78:331-338. 26. Fariello R, Shug A. Competitive inhibition by 3-aminopropane-sulfonic acid and gammaaminobutyric acid of carnitine transport in rat brain slices . Biochem Pharmacol . 1981;30:1012-1013.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Cultured Cells as a Screen for Novel Treatments of Alzheimer's Disease

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Publisher
American Medical Association
Copyright
Copyright © 1989 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.1989.00520470057027
Publisher site
See Article on Publisher Site

Abstract

Abstract • Two easily measured abnormal properties of fibroblasts from patients with Alzheimer's disease have been utilized to develop an in vitro test system for screening novel therapeutic agents for Alzheimer's disease. The abnormal properties selected for study were increased isoproterenol-stimulated cyclic adenosine monophosphate production and decreased pH (measured by the weak-acid distribution method). L-Carnitine was tested as a potential therapeutic agent, since it has been used to treat a variety of experimental metabolic encephalopathies. The addition of L-carnitine normalized both of these properties in the Alzheimer cells. Tissue culture may aid as a preliminary screen for identifying novel approaches to the treatment of Alzheimer's disease. References 1. Summers WK, Majovski LK, Marsh GM, Tachiki K, Kling A. Oral tetrahydroacridine in long term treatment of senile dementia Alzheimer type . N Engl J Med . 1986;315:1241-1245.Crossref 2. Ames BN. Dietary carcinogens and anticarcinogens . Science . 1983;221:1256-1264.Crossref 3. Baker AC, Ko L-W, Blass JP. Systemic manifestations of Alzheimer's disease . Age . 1988;11:60-65.Crossref 4. Johnson WG. The clinical spectrum of hexosaminidase deficiency diseases . Neurology . 1981;31:1453-1456.Crossref 5. Pettegrew JW, Nichols JS, Stewart RM. Fluorescence spectroscopy on Huntington's fibroblasts . J Neurochem . 1979;33:905-911.Crossref 6. Malow BA, Baker AC, Gleason PM, Blass JP. Carnitine in Alzheimer's disease fibroblasts and patients . Clin Res . 1987;35:579A. 7. L'Allemain G, Paris S, Poyssegur J. Growth factor action and intracellular pH regulation in fibroblasts . J Biol Chem . 1984;259:5809-5815. 8. McSwigan JD. Alzheimer's disease fibroblasts accumulate more cyclic AMP in response to β-adrenergic stimulation vs normal fibroblasts . Neurosci Abstr . 1986;12:1316. 9. Hanson DR, Sheppard JR. Hormone responsiveness in cultured human skin fibroblasts from individuals with Down syndrome and Alzheimer disease . Am J Hum Genet . 1979;31:49A. 10. Sims NR, Finegan JM, Blass JP, Bowen DM, Neary D. Mitochondrial function in brain tissue in primary degenerative dementia . Brain Res . 1987;436:30-38.Crossref 11. Sims NR, Finegan JM, Blass JP. Altered metabolic properties of cultured skin fibroblasts in Alzheimer's disease . Ann Neurol . 1987;21:451-457.Crossref 12. Peterson C, Ratan RR, Shelanski ML, Goldman JE. Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors . Proc Natl Acad Sci USA . 1986;83:7999-8001.Crossref 13. Rebouche CJ, Engel AG. Carnitine metabolism and deficiency syndromes . Mayo Clin Proc . 1983;58:533-540. 14. Seccombe DW, Snyder F, Parsons HG. L-Carnitine for methylmalonic aciduria . Lancet . 1982;2:1401.Crossref 15. Stumpf DA, Parker WD, Angeline C. Carnitine deficiency, organic acidemias, and Reye's syndrome . Neurology . 1985;35:1041-1045.Crossref 16. Coulter DL. Carnitine deficiency: a possible mechanism for valproate toxicity . Lancet . 1984;1:689.Crossref 17. Shug AL, Hayes B, Huth PJ, et al. Changes in carnitine-linked metabolism during ischemia, thermal injury, and shock . In: Frenkel RA, McGarry JD, eds. Carnitine Biosynthesis, Metabolism, and Functions . Orlando, Fla: Academic Press Inc, 1980:321-340. 18. Kim CS, Dorgan DR, Roe CR. L-Carnitine: therapeutic strategy for metabolic encephalopathy . Brain Res . 1984;310:149-153.Crossref 19. Costell M, Miguez MP, O'Connor JE, Grisdea S. Effect of hyperammonemia on the levels of carnitine in mice . Neurology . 1987;37:804-808.Crossref 20. Folts JD, Shug AL, Koke JR, Bittar N. Protection of the ischemic dog myocardium with carnitine . Am J Cardiol . 1978;41:1209-1214.Crossref 21. Peterson C, Goldman JE. Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors . Proc Natl Acad Sci USA . 1986;83:2758-2762.Crossref 22. Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain . Int J Clin Pharm Ther Toxicol . 1986;24:511-516. 23. Bremer J. Carnitine: metabolism and functions . Physiol Rev . 1983;63:1420-1480. 24. Dolezal V, Tucek S. Utilization of citrate, acetylcarnitine, acetate, pyruvate, and glucose for the synthesis of acetylcholine in rat brain slices . J Neurochem . 1981;36:1323-1330.Crossref 25. Blum K, Seifter E, Seifter J. The pharmacology of d- and l-carnitine: comparison with choline and acetylcholine . J Pharmacol Exp Ther . 1971;78:331-338. 26. Fariello R, Shug A. Competitive inhibition by 3-aminopropane-sulfonic acid and gammaaminobutyric acid of carnitine transport in rat brain slices . Biochem Pharmacol . 1981;30:1012-1013.Crossref

Journal

Archives of NeurologyAmerican Medical Association

Published: Nov 1, 1989

References