All six isoforms of tau are highly hydrophilic and are, thus, soluble and heat stable. In a normal mature neuron tubulin is present in over tenfold excess of tau.
Hence, tau-fyn interactions could play a pathogenic role in AD. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network.
Our results suggest that the pathological mechanisms underlying AD, that result in increased tau phosphorylation, may disrupt the physiological relationship between tau phosphorylation and fyn. Pathological Forms and States of Tau Abnormal Hyperphosphorylation and Oligomerization of tau Neurofibrillary degeneration of abnormally hyperphosphorylated tau not only occurs in AD brain but is also seen in a family of related neurodegenerative diseases, called tauopathies, such as fronto-temporal dementia with Parkinsonism linked to chromosome 17 FTDP caused by tau mutations, Pick disease, corticobasal degeneration, dementia pugilistica, and progressive supranuclear palsy.
Up until recently [ 42 ] this oligomeric tau was referred to as cytosolic tau, amorphous tau, and sedimentable cytosolic abnormally hyperphosphorylated tau [ 1920314143 - 47 ].
PhillipsMichael J. In frontotemporal dementia with Parkinsonism-linked to chromosome 17 and tau pathology FTDPtauseveral missense mutations in tau cosegregate with the disease [ 26 - 28 ]. Both the extra repeat Repeat 2 in the 4R taus and the amino terminal inserts N1 and N2 enhance the binding of tau to tubulin, which makes 2N4R tau tauand 0N3Rtau tau, the fetal tau the relatively most and the least effective in promoting microtubule assembly [ 2122 ].
Studies on the role of tau in neurodegeneration and therapeutic targets based on this pathology have been the subject of several recent reviews by us and others [ 9 - 17 ]. Notably, however, there was a significant correlation between fyn and phosphorylated tau at specific phospho-epitopes in control, but not in AD brain.
Therefore it is of interest to determine which of the motifs is critical for tau-fyn interactions. To date, in aged and in cognitively impaired animals the neurofibrillary degeneration of abnormally hyperphosphorylated tau has been found only sparsely. Electronic supplementary material The online version of this article doi: In AD brain all of the six tau isoforms are hyperphosphorylated and aggregated into PHF [ 429 - 33 ].
While conformational changes [ 34 - 36 ] and truncation of tau [ 37 - 39 ] following its hyperphosphorylation [ 40 ]have been reported in AD, the most established and the most compelling cause of dysfunctional tau in AD and related tauopathies is the abnormal hyperphosphorylation of this protein [ 42031 ].
The non-receptor-associated tyrosine kinase fyn is located at the dendrite in neurons, where it was recently shown to interact with tau to stabilise receptor complexes at the post-synaptic density.
Tau has seven such motifs, some overlapping in tandem, within the proline-rich region in the N-terminal half. These six tau isoforms differ in containing three 3R taus or four 4R taus microtubule binding repeats R of 31—32 amino acids in the carboxy terminal half and one 1Ntwo 2Nor zero 0N amino terminal inserts of 29 amino acids each; the extra repeat in 4R tau is the second repeat R2 of 4R taus.
Abstract Tau is the major microtubule associated protein MAP of a mature neuron. In support of this suggestion, tau has been shown to associate with synaptic proteins, such as post-synaptic density protein 95 PSD and fyn [ 14 ].
The generation of plasmids encoding 2N4R tau containing proline-to-alanine substitutions at residues PA or PA of tau has been described previously [ 10 ]. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain.
In every one of these tauopathies the neurofibrillary changes are made up of abnormally hyperphosphorylated tau and their occurrence in the neocortex is associated with dementia.
The AD cytosolic abnormally hyperphosphorylated tau AD P-tau does not bind to tubulin and promote microtubule assembly, but instead it inhibits assembly and disrupts microtubules Fig. These isoforms are coded by a single gene on chromosome 17 and are generated by alternative splicing of its pre-mRNA [ 2 ].
Here we report the identification of critical proline residues, Pro, Pro, and Pro, located within the fifth and sixth Pro-X-X-Pro motifs in the proline-rich region of tau, that are important for its binding to fyn. Microtubule associated proteins, hyperphosphorylation of tau, microtubule assembly, neurofibrillary tangles, paired helical filaments, tau truncation Introduction Tau is the major microtubule associated protein MAP of a normal mature neuron.
Neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of AD and related tauopathies [ 6 - 8 ].
The smallest size tau isoform, which lacks both the two amino terminal inserts and the extra microtubule binding repeat 0N3R; tauis the only form that is expressed in fetal human brain.
This article has been cited by other articles in PMC. These data indicate that the mis-localisation of fyn caused by truncated tau rescued amyloid-induced phenotypes.
Recent evidence however, suggests that tau is also present in dendrites where it may play a role in synaptic function [ 1 — 3 ]. Feb 15, · Parallel cultures of hTERT cells were transiently transfected with plasmids expressing a human APP gene carrying both the NL-APP KN/ML (Swedish) and VI (London) mutations or the VI APP mutation.
The empty vectors served as controls. May 28, · The researchers then injected these two strains into transgenic mice expressing full-length human mutant tau (PS), which causes inherited tauopathies. After three weeks, they looked at pathology in the brain.
Tau in Alzheimer Disease and Related Tauopathies. Khalid Iqbal Transgenic rats expressing human tau truncated both N- and C-terminally tau – show a marked Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.
J Alzheimers Dis. ; – Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides.
Amounts of expression plasmids were held constant while the concentration of siA10 was varied from 0 to 10 µg per well. (C) Silencing tau with shRNA plasmid expressed from the tRNA‐valine promoter.
Shown is a western blot analysis of cells cotransfected with mutant. tau around these motifs would correlate with levels of fyn in human post-mortem brain tissue from unaffected individuals or patients with AD.
Materials and methods Plasmids A plasmid expressing the longest isoform of human CNS tau containing two N-terminal inserts and four microtubule-binding repeats (2N4R) has been described previously .Plasmids expressing human tau to further understand alzheimers disease