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Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.).
Alzheimer’s disease (AD) is by far the most common form of dementia; being more prevalent than vascular dementia, mixed dementia, Lewy body dementia (LBD) and frontotemporal dementia (FTD).
Tau is well established as a microtubule-associated protein in neurons.
However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies.
Alternative splicing of exon 10 in the microtubule binding domain (MTBD), results in 3R or 4R tau isoforms.
The C-terminal region is common to all six human CNS tau isoforms.
exons 2 and 3 each encode an insert of 29 amino acids in the amino terminal region of tau, and exon 3 is not transcribed in the absence of exon 2.
Consequently, alternative splicing yields six tau isoforms that can be differentiated by the presence of zero, one or two N-terminal inserts (0N, 1N, or 2N, respectively), and the presence of either three (3R) or four (4R) microtubule binding repeats in the C-terminal half of tau (Fig. Distinct amino acid sequences encoded by exons 2 and 3 in the N-terminal region of tau are either excluded (0N), or differentially included giving rise to 1N (exon 2) or 2N (exons 2 and 3) tau isoforms.
The central region of tau comprises the proline-rich domain (PRD).
It has also been proposed that tau interacts with components of the neural plasma membrane through its N-terminal domain, presumably via an interaction with the membrane-binding protein annexin A2 .
In addition, tau isoforms in possession of different numbers of N-terminal inserts display distinct protein interaction patterns.
For example, apolipoprotein A1 preferentially, if not exclusively, binds to 2N tau isoforms, whereas β-synuclein and synaptophysin more readily interact with 0N tau isoforms [The proline-rich domain of tau harbours seven Pro-X-X-Pro (PXXP) motifs, providing potential recognition sites for Src homology-3 (SH3)-containing proteins including the Src family of protein kinases, such as Lck, Fgr, and Fyn, and other diverse proteins including bridging integrator 1 (Bin1), peptidylprolyl ] and these interactions are likely to have roles in modulating the signalling functions of tau.