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

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 β 25 - 35) were shown to exacerbate tree-radical damage, while melatonin reduced this effect. The aim of the present study was: ( i ) to investigate the conditions detennining the toxicity of Al and A β  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 β 25 - 35 caused lipid peroxidation in the presence of the iron (II) ion (Fe 2+ , Al being more toxic than A β 25 - 35. 2. A β 25 - 35 attenuated the lipid peroxidation promoted by Al. 3. Hydrogen peroxide (H 2 O 2 greatly exacerbated the toxicity of Al and A β 25 - 35. 4. Melatonin prevented lipid peroxidation by Al and A β  25 - 35 in the absence of H 2 O 2 , but only reduced the process when H 2 O 2 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 peroxidatian in the Iysosomes. 2. In response, the normal synthetic pathway of amyloid protein is altered to produce A β 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 H 2 O 2 . 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 β , 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.