The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome

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Excerpt

Tau is a microtubule‐associated protein encoded by a single gene (MAPT) on chromosome 17q21.3 1 and ubiquitously expressed during early embryonic development 2. Alternative splicing generates six isoforms, which are present in the adult human brain 1. Posttranslational tau modifications play an important role in tauopathies and normal function. Tau contains at least 85 potential serine (Ser), threonine (Thr) and tyrosine phosphorylation sites 2. Normal tau is phosphorylated on two or three residues in contrast to hyperphosphorylated tau in neurodegenerative disorders, which is phosphorylated at least on 8–12 residues 1.
Both the phosphorylation status and isoform expression of tau are developmentally regulated 2 and both have important roles for brain physiology and brain development. Indeed, evidence is accumulating that major signalling pathways involved in brain development may be implicated in pathologic ageing as well 3. Even late‐onset AD might be considered as a disorder of aberrant neural development with pathological changes that are set up at early stages of development before the appearance of any symptoms 4.
Down syndrome (DS) or trisomy 21 represents one of the most common genetic causes of cognitive impairment with an incidence of approximately 1–1.4/1000 live birth 5. Histological studies revealed disturbed proliferation and migration of neurons and glia cells in DS developing brains, resulting in reduced cortical volume, delayed myelination and, consequently, mental retardation 6. Individuals with DS are prone to develop AD‐like pathology early in their life 12, and thus represent an interesting model of premature ageing.
In the present work we focused on the developmental changes in the phosphorylation patterns of tau in the normal developing human brains and in developing brains of individuals with DS. The rationale of our work is that the developmental changes of tau protein might predict the pathological change of tau in adults and our aim is to describe the developmental expression of phosphorylated tau in normal developing brains in comparison to DS brains.
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