Tau Protein Phosphorylated at Threonine-231 is Expressed Abundantly in the Cerebellum in Prion Encephalopathies.

BACKGROUND: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called "prion", which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-ß protein plaques are associated with memory loss and cognitive impairment in patients. OBJECTIVE: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. METHODS: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. RESULTS: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum. CONCLUSION: We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion.

The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease.

We previously demonstrated that, in the early stages of tau processing in Alzheimer's disease, the N-terminal part of the molecule undergoes a characteristic cascade of phosphorylation and progressive misfolding of the proteins resulting in a structural conformation detected by Alz-50. In this immunohistochemical study of AD brain tissue, we have found that C-terminal truncation of tau at Asp-421 was an early event in tau aggregation and analyzed the relationship between phospho-dependent tau epitopes located at the C-terminus with truncation at Glu-391. The aim of this study was to determine whether C-terminal truncation may trigger events leading to the assembly of insoluble PHFs from soluble tau aggregates present in pre-tangle cells. Our findings suggest that there is a complex interaction between phosphorylated and truncated tau species. A model is presented here in which truncated tau protein represents an early neurotoxic species while phosphorylated tau species may provide a neuroprotective role in Alzheimer's disease.

Identification of N-terminally truncated pyroglutamate amyloid-ß in cholesterol-enriched diet-fed rabbit and AD brain.

The main amyloid-ß peptide (Aß) variants detected in the human brain are Aß1-40 and Aß1-42; however, a significant proportion of Aß in Alzheimer's disease (AD) brain also consists of N-terminal truncated/modified species. AßN3(pE), Aß peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular Aß deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular Aß accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of AßN3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected AßN3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting Aß peptides in a suitable non-transgenic animal model.