Aluminum, altered transcription, and the pathogenesis of Alzheimer's disease

The etiology of some, if not all, cases of Alzheimer's disease is linked to a mutation in the proximal portion of the long arm of chromosome 21∶21q11.2 → 21q22.2. While the functional consequences of the mutation are unknown, we speculate that one consequence of the mutation is loss of the natural barriers and intracellular ligands for aluminum. As a result, aluminum gains access to several brain sites including the nuclear compartment in certain neurons of the central nervous system.Both sporadic and familial Alzheimer's disease are associated with an increased compaction of DNA within chromatin as measured by physical shearing and resistance to digestion by micrococcal nuclease and DNase I. There is also an increase in linker histone Hl(o) content on dinucleosomes released by light (3-5% ASN) micrococcal nuclease digestion, and an increase in the affinity of histone Hl(o) for DNA as measured by a salt elution technique. The change in enzyme accessibility to chromatin also involves the 5' promoter region of at least one physiologically important gene: the gene which codes for the low molecular weight moiety of neurofilament (NF-L). The conformation change involving the 5' regulator region probably reduces transcription because the pool size of the mRNA coding for NF-L is reduced to 14% of age matched control in cerebral grey matter. Reduced transcription may account for many disorders in cellular metabolic processes including the regulation of phosphorylation, calcium homeostasis, free radical metabolism, proteolysis and neurotransmitter metabolism.The experimental evidence indicates that one important toxic action of aluminum in Alzheimer's disease neocortex is to increase the binding of histones, particularly Hl(o), to DNA which results in increased compaction of chromatin and reduced transcription. The supporting evidence includes: (1) A statistically reliable correlation between the aluminum to DNA ratio on intermediate euchromatin and the amount of highly condensed heterochromatin found in a given preparation from Alzheimer affected neocortex (Crapperet al., 1980). (2) A nine-fold increase in aluminum content in Alzheimer's disease in the di- and tri- nucleosome fraction released by light micrococcal nuclease digestion of nuclei from cerebral grey matter compared to age matched controls. Compared to age matched control dinucleosomes, the Alzheimer affected dinucleosomes contain an increased abundance of the linker histone Hl(o) and an increased propo