Ubiquitin is associated with early truncation of tau protein at aspartic acid(421) during the maturation of neurofibrillary tangles in Alzheimer's disease.

Pathological processing of tau protein during the formation and maturation of neurofibrillary tangles (NFTs) includes abnormal phosphorylation, conformational changes and truncation of the C-terminus at aspartic-acid(421) (apoptotic product) and glutamic-acid(391) residues. Abnormal phosphorylation and misfolding may serve as recognition signals for ubiquitin-targeting and proteosomal processing. For this reason, we sought to determine whether ubiquitin-targeting of tau is associated with particular tau modifications that herald specific stages of NFTs maturation in the hippocampus of Alzheimer's disease cases. Using multiple tau antibodies, we found that 30% of the total load of NFTs is ubiquitin-associated. As reported previously ubiquitin immunoreactivity was associated with markers of phosphorylated tau in certain NFTs; however, a strong association was also found between ubiquitin and the earliest known truncation event at aspartic-acid(421) . These findings indicate that tau protein in the NFTs may be dually subjected to both apoptotic and proteosomal processing. By contrast ubiquitin immunoreactivity was poorly associated with truncation of tau at glutamic-acid(391) , suggesting that this proteolytic event may be independent of proteosomal activity. It would appear, therefore, that ubiquitin targeting of tau protein occurs at NFTs in the early and intermediate stages of the maturation.

Planum temporale analysis via a new volumetric method in autoptic brains of demented and psychotic patients.

Investigations of alterations in brain asymmetry often focus on the planum temporale of patients with schizophrenia. Data also suggest changes in laterality of demented patients associated with a more marked impairment of the left hemisphere. Our study was performed on autoptic brain tissue of 84 patients, out of which there were 25 non-demented non-psychotic controls, 50 demented patients (34 Alzheimer disease, 9 multi - infarct dementia and 7 mixed-type dementia patients) and 9 people with schizophrenia. The plana temporalia were evaluated via a new volumetric method using dental resin matter. Areas, cortical thickness and volumes of the right and left planum temporale were evaluated without normalization to brain weight in 60 patients and with normalization in 24 people. In controls, a mild right/left laterality of areas, cortical thickness and volumes was found. Moreover, in control women the areas of the left planum temporale were smaller than those observed in control men. The shifts to left/right laterality of areas and volumes were found in all demented groups. In the more numerous Alzheimer group, the change in laterality of an area was associated with a mild decrease on the right and a mild increase on the left side. In contrast, marked but only bilateral area shrinkage as well as reduced cortical thickness and brain volumes were observed in schizophrenic patients.

Lateralization of 17beta-hydroxysteroid dehydrogenase type 10 in hippocampi of demented and psychotic people.

OBJECTIVE: The multifunctional mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 could play a role in the development of Alzheimer disease via its high-affinity binding to amyloid-beta peptides and its overexpression. METHODS: We evaluated the specificity of alterations in mRNA/enzyme expression levels in human right and left hippocampi. RESULTS: We observed a trend towards right/left laterality in nondemented nonpsychotic controls; however, the degree of asymmetry was higher for mRNA when compared to enzyme expression levels. In Alzheimer disease and schizophrenia, significant shifts to left/right asymmetry were found and the changes were associated with more marked increases in mRNA/enzyme expression in the left hemisphere. On the other hand, no alterations were observed in people with multi-infarct dementia. CONCLUSION: Our results support studies reporting an impairment of mitochondria in Alzheimer disease or schizophrenia and a higher vulnerability of the dominant hemisphere to pathological processes. Overexpression of the enzyme could be used to distinguish Alzheimer disease from multi-infarct dementia.