Stages of Pathological Tau-Protein Processing in Alzheimer’s Disease: From Soluble Aggregations to Polymerization into Insoluble Tau-PHFs
Hyperphosphorylation and truncation have been proposed as key events in the abnormal tau-protein processing leading to the genesis of paired helical filaments. A recent hypothesis involving conformational changes has been emerging. However, the majority of studies have been based on the analysis of overt tangles. All the existing antibodies have been raised against normal, pathological tau protein, or intracellular tangles. It is possible that only those events occurring massively may be detected when observations are restricted to this type of structure, therefore, missing less-evident events. In general, it has been difficult to determine the early stages of tau processing in Alzheimer’s disease. By the use of selected tau markers and confocal microscopy in double and triple immunolabeling and the combination with thiazin red, we have been able to determine a morphological model and the underlying molecular mechanism involved in early stages of tau-protein abnormal processing. This molecular mechanism is characterized by a hierarchical sequence of events of phosphorylation and truncation resulting in conformational misfolding along the tau molecule. We have included some speculations regarding the possible triggers of such a cascade of pathological changes of tau based on the hypothesis of truncated tau as a highly stable tau fragment with a special high affinity to bind tau monomers. Relationships between phosphorylation and the truncated mechanism are also discussed.
KeywordsPaired Helical Filament Triple Immunolabeling AT100 Epitope Intracellular Tangle Modeling Early Stage
Authors express their gratitude to Dr. P. Davies (Albert Einstein College of Medicine, Bronx, NY, USA) for the generous gift of mAbs TG-3, Alz-50, and MC1, Mr. José L. Fernández for handling of the brain tissue, and Ms. Maricarmen De Lorenz for her secretarial assistance. This work was financially supported by CONACyT grants, No. 47630 (to R.M.). Thanks to Dr. Ellis Glazier for editing the English-language text.
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