engleski

Phosphorylation of tau protein during early development and progression of Alzheimer's disease

Background and Aim: Some of our previous findings suggested that abnormal hyperphosphorylation of tau protein in Alzheimer's disease (AD) may result from the reactivation of fetal plasticity mechanisms. However, the phosphorylation of tau protein in the fetal telencephalon remained poorly investigated. Therefore, the aim of this study was to examine the presence and distribution of AT8-immunoreactivity (AT8-ir) in the human brain during several stages of fetal development, and to compare with a normal elderly, mildly cognitively impaired (MCI) and AD brain. Methods: The AT8 mouse monoclonal anti-human tau antibody (Innogenetics, Temse, Belgium) was employed in indirect-immunocytochemistry (dilution 1:200) and Western blot (dilution 1:500) on samples of thirteen fetal human brains, two adult control and two MCI, as well as ten AD cases. AT8 reacts with tau only when multiple sites around Ser202, including Ser199, Ser202 and Thr205, are phosphorylated. Single phosphorylation of any of the residues is not enough for AT8 reactivity. Thus, AT8-ir is useful in detecting phosphorylation of Ser202/Thr205 for proline-directed kinases. As shown by Braak and collaborators, AT8-ir permit the evaluation of neuronal changes well before the actual formation of neurofibrillary tangles and neuropil threads. Results: Specific AT8-ir was found already at 10th week of gestation (w.g.), which was the earliest fetal stage examined. AT8-ir was most prominent in the lower subplate zone at about 18th w.g. and in the upper subplate around 20th w.g. ; it then gradually diminished and disappeared to the end of 32nd w.g., implying that this phosphorylation of tau is most pronounced in a distal part of growing cortical afferents. During mid-gestation, the fornix as well as a subset of callosal commissural fibers were unambiguously AT8-ir, while the internal capsule remained unstained in this period, supporting the same suggestion. Unlike in control cases, in MCI brains many entorhinal and hippocampal neurons, as well as some neurons of the temporal isocortex, presented initial cytoskeletal changes such as AT8-ir tortuous varicose apical dendrites and curved, thickened dendrites. In these two cases, we have also found previously poorly described AT8-ir fibers in the transentorhinal/entorhinal cortex and hippocampal formation. Beaded- or rod-like AT8-ir was most conspicuous in the perforant fascicle and in CA1 axons projecting into the subiculum. In the AD brain AT8-immunoreactive neurons were characterized by coarse AT8-ir granules, but most tangle-bearing neurons were not AT8-ir. Conclusions: The present work provides data on the normal developmental pattern of phosphorylation of tau protein in the fetal human brain. Results obtained in MCI and AD cases clearly show a layer- and stage-specific pattern of tau hyperphosphorylation during the progression of Alzheimer's disease. Since this AT8-ir is identical to that found in the fetal brain, we may conclude that some proline-directed kinases are abnormally reactivated during the early course of AD.

phosphorylation; tau proteins; fetal development; aging; mild cognitive impairment; Alzheimer's disease; cerebral cortex; plasticity

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