THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES New Evidence for an Active Role of Aluminum in Alzheimer's Disease

Application of molecular biological techniques and sensitive elemental analysis have produced new evidence implicating aluminum as an important factor in down regulation of neuronal protein metabolism. Aluminum in Alzheimer's disease may act by electrostatically crosslinking proteins, particularly the methionine containing histone Hl°, and DNA. The consequence of such crosslinking is reduced transcription of at least one neuron specific gene, the low molecular weight component of neurofilaments. In the superior temporal gyrus in Alzheimer's disease, down regulation of this gene occurs in approximately 86% of surviving neurons and, therefore, aluminum must be considered as having an active role in the pathogenesis. Epidemiological studies are reviewed that independently support the hypothesis that environmental aluminum is a significant risk factor. Preliminary evidence also suggests that a disorder in phosphorylation may be an important initiating factor. RESUME: Nouvelles observations en faveur d'un role actif de Paluminium dans la maladie d'Alzheimer L'application de techniques de biologie moleculaire et de methodes sensibles d'analyse 61ementaire nous ont permis de mettre en evidence de nouveaux indices impliquant Faluminium comme facteur important dans la regulation a la baisse du metabolisme des prolines neuronales. L'aluminium pourrait agir dans la maladie d'Alzheimer (MA) par la formation de ponts electrostatiques entre les proteines, particulierement l'histone Hl° contenant de la methionine, et l'ADN. La consequence de Fetablissement de ces ponts est de reduire la transcription d'au moins une gene specifique au neurone, celui de la composante de poids moleculaire bas des neurofilaments. Dans le gyrus temporal supeYieur des patients atteints de MA, la regulation a la baisse de ce gene survient dans a peu pres 86% des neurones restants. On doit done consideYer que Faluminium joue un role actif dans la pathogenese de la maladie. Nous revoyons les 6tudes epidemiologiques qui supportent de fagon independante l'hypothese que Faluminium environnemental est un facteur de risque significatif. Des donnees preliminaires suggerent egalement qu'une anomalie de la phosphorylation peut etre un facteur important amor§ant le processus. Can. J. Neurol. Sci. 1989; 16:490-497 Despite intensive investigation world-wide, the etiology of senile and presenile dementia of the Alzheimer type remains unknown. The etiology is most probably multifactorial and dependent upon genetic and environmental determinants. Applications of molecular biological techniques together with neurochemistry are beginning to provide a more precise understanding of the molecular events underlying this baffling neurodegenerative disorder. Among the environmental factors implicated in Alzheimer's disease (AD), aluminum has often been suggested but analytical difficulties and the limitations of instrumental detection continue to contribute to a controversy regarding its role in AD. The new evidence presented here for a role of aluminum has resulted from an examination of nuclear mechanisms involved in the regulation of gene expression. Historically, aluminum was reported to be a selective neurotoxin in 1897 and was shortly thereafter recognized as a human poison which caused loss of memory, jerking movements and impaired coordination. Intensive modern investigations into aluminum toxicity were initiated by the work of Klatzo et al and Terry and Pena who reported that intracranial injection of small doses of soluble aluminum salts in rabbit induced an encephalopathy associated with the intraneuronal accumulation of dense bundles of 10 nm filaments. Sections examined with a Norelco Electron Probe Analyser detected a trace of aluminum in the affected areas in rabbit brain, but similar scans of autopsied human neurofibrillary tangles from AD patients did not reveal even traces of aluminum. The apparent absence of increased amounts of the element and the morphological differences between the paired helical filaments of AD brain and the 10 nm straight filaments of aluminum induced neurofibrillary degeneration made aluminum an unlikely factor in the disease. The development of the very sensitive and reproducible technique of flame atomic absorption spectrophotometry in the From the Department of Physiology, University of Toronto, Toronto Reprint requests to: D.R. Crapper McLachlan, Department of Physiology, Room 3318, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8