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A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin.
S Afr Med J. 1997 Sep; 87(9):1111-5.SA

Abstract

OBJECTIVES

Although Alzheimer's disease (AD) is the leading cause of dementia in developed countries, there is an as yet unexplained lower prevalence of the disease in parts of Africa. AD is characterised by a catastrophic loss of neurons; free radicals (oxidative toxins) have been implicated in the destruction of the cells through the process of lipid peroxidative damage of cell membranes. Previously aluminium (Al) and a fragment of beta amyloid (A beta 25-35) were shown to exacerbate free-radical damage, while melatonin reduced this effect. The aim of the present study was: (i) to investigate the conditions determining the toxicity of Al and A beta 25-35; and (ii) to assess whether melatonin could attenuate the damage done by both aluminium and the amyloid fragment, thus suggesting a pathway for the aetiology of AD.

DESIGN

An in vitro model system was used in which free radicals were generated, causing lipid peroxidation of platelet membranes, thus simulating the disease process found in the brain.

RESULTS

1. Al and A beta 25-35 caused lipid peroxidation in the presence of the iron (II) ion (Pe2+), Al being more toxic than A beta 25-35. 2. A beta 25-35 attenuated the lipid peroxidation promoted by Al. 3. Hydrogen peroxide (H2O2) greatly exacerbated the toxicity of Al and A beta 25-35. 4. Melatonin prevented lipid peroxidation by Al and A beta 25-35 in the absence of H2O2, but only reduced the process when H2O2 was present.

CONCLUSIONS

In the light of the results obtained from the present study, the following hypotheses are formulated. 1. In AD, excessive quantities of Al are taken up into the brain, where the Al exacerbates iron-induced lipid peroxidation in the lysosomes. 2. In response, the normal synthetic pathway of amyloid protein is altered to produce A beta fragments which attenuate the toxicity of Al. In the process of sequestering the Al and iron, immature plaques are formed in the brain. 3. Microglia are activated, in an attempt to destroy the plaques by secreting reactive oxygen species such as H2O2. At this point in the disease process, lipid peroxidation causes a catastrophic loss of brain cells. 4. Melatonin, together with other free radical scavengers in the brain, reduces the free-radical damage caused by Al and A beta, except in the latter stages of the disease process. Since melatonin is produced by the pineal gland only in the dark, the excess of electric light in developed countries may help explain why AD is more prevalent in these countries than in rural Africa.

Authors+Show Affiliations

Department of Chemical Pathology, University of Stellenbosch, Tygerberg, W Cape.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9358827

Citation

van Rensburg, S J., et al. "A New Model for the Pathophysiology of Alzheimer's Disease. Aluminium Toxicity Is Exacerbated By Hydrogen Peroxide and Attenuated By an Amyloid Protein Fragment and Melatonin." South African Medical Journal = Suid-Afrikaanse Tydskrif Vir Geneeskunde, vol. 87, no. 9, 1997, pp. 1111-5.
van Rensburg SJ, Daniels WM, Potocnik FC, et al. A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin. S Afr Med J. 1997;87(9):1111-5.
van Rensburg, S. J., Daniels, W. M., Potocnik, F. C., van Zyl, J. M., Taljaard, J. J., & Emsley, R. A. (1997). A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin. South African Medical Journal = Suid-Afrikaanse Tydskrif Vir Geneeskunde, 87(9), 1111-5.
van Rensburg SJ, et al. A New Model for the Pathophysiology of Alzheimer's Disease. Aluminium Toxicity Is Exacerbated By Hydrogen Peroxide and Attenuated By an Amyloid Protein Fragment and Melatonin. S Afr Med J. 1997;87(9):1111-5. PubMed PMID: 9358827.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin. AU - van Rensburg,S J, AU - Daniels,W M, AU - Potocnik,F C, AU - van Zyl,J M, AU - Taljaard,J J, AU - Emsley,R A, PY - 1997/11/14/pubmed PY - 1997/11/14/medline PY - 1997/11/14/entrez SP - 1111 EP - 5 JF - South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde JO - S Afr Med J VL - 87 IS - 9 N2 - OBJECTIVES: Although Alzheimer's disease (AD) is the leading cause of dementia in developed countries, there is an as yet unexplained lower prevalence of the disease in parts of Africa. AD is characterised by a catastrophic loss of neurons; free radicals (oxidative toxins) have been implicated in the destruction of the cells through the process of lipid peroxidative damage of cell membranes. Previously aluminium (Al) and a fragment of beta amyloid (A beta 25-35) were shown to exacerbate free-radical damage, while melatonin reduced this effect. The aim of the present study was: (i) to investigate the conditions determining the toxicity of Al and A beta 25-35; and (ii) to assess whether melatonin could attenuate the damage done by both aluminium and the amyloid fragment, thus suggesting a pathway for the aetiology of AD. DESIGN: An in vitro model system was used in which free radicals were generated, causing lipid peroxidation of platelet membranes, thus simulating the disease process found in the brain. RESULTS: 1. Al and A beta 25-35 caused lipid peroxidation in the presence of the iron (II) ion (Pe2+), Al being more toxic than A beta 25-35. 2. A beta 25-35 attenuated the lipid peroxidation promoted by Al. 3. Hydrogen peroxide (H2O2) greatly exacerbated the toxicity of Al and A beta 25-35. 4. Melatonin prevented lipid peroxidation by Al and A beta 25-35 in the absence of H2O2, but only reduced the process when H2O2 was present. CONCLUSIONS: In the light of the results obtained from the present study, the following hypotheses are formulated. 1. In AD, excessive quantities of Al are taken up into the brain, where the Al exacerbates iron-induced lipid peroxidation in the lysosomes. 2. In response, the normal synthetic pathway of amyloid protein is altered to produce A beta fragments which attenuate the toxicity of Al. In the process of sequestering the Al and iron, immature plaques are formed in the brain. 3. Microglia are activated, in an attempt to destroy the plaques by secreting reactive oxygen species such as H2O2. At this point in the disease process, lipid peroxidation causes a catastrophic loss of brain cells. 4. Melatonin, together with other free radical scavengers in the brain, reduces the free-radical damage caused by Al and A beta, except in the latter stages of the disease process. Since melatonin is produced by the pineal gland only in the dark, the excess of electric light in developed countries may help explain why AD is more prevalent in these countries than in rural Africa. SN - 0256-9574 UR - https://www.unboundmedicine.com/medline/citation/9358827/A_new_model_for_the_pathophysiology_of_Alzheimer's_disease__Aluminium_toxicity_is_exacerbated_by_hydrogen_peroxide_and_attenuated_by_an_amyloid_protein_fragment_and_melatonin_ L2 - https://medlineplus.gov/alzheimersdisease.html DB - PRIME DP - Unbound Medicine ER -