Chromatin structure and gene expression in Alzheimer's disease.

Light micrococcal nuclease digestion was used to examine DNA associated with nucleosome populations isolated from Alzheimer's disease (AD) affected superior temporal lobe neocortical nuclei. 46.1% of the immediate 5' upstream DNA sequence of the single copy neurofilament light chain (NF-L) gene was found to be associated with a mononucleosome fraction in control neocortices.

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.

The molecular mechanisms of scrapie encephalopathy and relevance to human neurodegenerative disease.

We have investigated alterations in the structure and function of nuclei isolated from normal and pathological brains in a number of neurodegenerative diseases including scrapie and Alzheimer's disease. Here we summarize both general and specific changes in chromatin structure, gene expression, and neuropathological features for each encephalopathy and compare them in terms of their molecular biological similarities and differences. While both scrapie and Alzheimer's disease share a number of common alterations in genomic organization and gene activity during the pathogenic process, each neurological disease appears to operate on fundamentally different mechanisms.

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 H1(0), and DNA. The consequence of such crosslinking is reduced transcription of at least one neuron specific gene, the low molecular weight component of neurofilaments.

Linker histone-DNA complexes: enhanced stability in the presence of aluminum lactate and implications for Alzheimer's disease.

The binding of human brain linker histone proteins to a radiolabelled human Alu repetitive element was examined by mobility shift assay. Analysis of the complexes formed from protein extracts of whole neocortical nuclei, under physiological conditions in vitro revealed that linker histone H1(0) has the highest affinity for the Alu DNA sequence. The linker histone-DNA complexes assembled in the presence of aluminum lactate were more resistant to sodium chloride-induced dissociation than those formed in the presence of sodium lactate.

Selective messenger RNA reduction in Alzheimer's disease.

The relative abundance of 7 messenger RNAs extracted from Alzheimer and control neocortex were examined by Northern and quantitative dot blot analysis. The average yield of mRNA coding for NF-L, the 68-kDa moiety of neurofilament protein, was reduced to 27% of control when expressed as the percentage of total RNA or 14% when expressed per gram of neocortex. In contrast, the yields of 6 other messenger RNAs fell into two categories: those which were statistically significantly reduced to about 65% of control and those which were not reduced when expressed as percentage of total RNA.

Alterations in human linker histone-DNA binding in the presence of aluminum salts in vitro and in Alzheimer's disease.

Sodium cations were employed to electrostatically displace chromosomal proteins from DNA. Increasing the ambient ionic concentration resulted in a characteristic dissociation pattern of chromatin which was analyzed on polyacrylamide gels. This method of sodium chloride extraction of nuclei in vitro has been used to investigate the state of compaction of chromatin in normal and Alzheimer affected neocortical nuclei and in control nuclei treated with aluminum lactate in vitro.

Chromatin structure in scrapie and Alzheimer's disease.

Scrapie affected brains exhibit a number of pathological features in common with the human neurodegenerative condition, Alzheimer's disease. The present report describes studies on chromatin structure seen in these two disease processes. Chromatin associated proteins influence transcriptional activity of DNA through an effect upon chromatin structure.

Chromatin structure in dementia.

Nuclei extracted from neocortex of patients with Alzheimer's disease and treated with micrococcal nuclease release a population of dinucleosomes that contain an increase in the linker histones H1o and H1oo . Five other degenerative brain diseases that clinically resemble Alzheimer's disease do not result in these changes, although Pick's disease is associated with an increase in H1 on dinucleosomes. Histones from nuclei of patients with Alzheimer's disease are also more resistant to salt-induced release from chromatin than are those from age-matched control subjects.

Changes in chromatin structure associated with Alzheimer's disease.

The enzyme micrococcal nuclease was used to examine the accessibility of chromatin extracted from brains of 13 patients with senile and presenile dementia of the Alzheimer type. Compared with chromatin extracted from brains of 8 patients without neurological signs or brain pathology and brains of 7 patients with nonAlzheimer dementia, Alzheimer chromatin was less accessible to this enzyme. Reduced accessibility was reflected by a reduced yield of mononucleosomes in comparison with dinucleosomes and larger oligomers.