Tau has seven such motifs, some overlapping in tandem, within the proline-rich region in the N-terminal half. The neurofibrillary degeneration of the Alzheimer type is primarily seen in human neurodegenerative disorders.
Normal brain tau contains 2—3 moles of phosphate per mole of the protein [ 19 ], which appears to be optimal for its interaction with tubulin and the promotion of microtubule assembly.
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.
Like MAP1 and MAP2, tau is a phosphoprotein and its biological activity is regulated by the degree of its phosphorylation [ 18 - 20 ]. Fyn also co-localises with tau in a proportion of neurons containing tau tangles in AD and fyn is also a tau kinase.
In cultured cells overexpression of tau can cause microtubule bundling. In frontotemporal dementia with Parkinsonism-linked to chromosome 17 and tau pathology FTDPtauseveral missense mutations in tau cosegregate with the disease [ 26 - 28 ].
Published online May This toxic behavior of the AD P-tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation of diseased tau converts it into a normal-like protein [ 2050 - 52 ]. Neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of AD and related tauopathies [ 6 - 8 ].
Subsequently, a detailed study in mouse brain demonstrated that a small proportion of tau interacts with fyn in dendrites [ 1 ]. Hyperphosphorylation of tau depresses this biological activity of tau. 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 mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network.
Up until recently [ 42 ] this oligomeric tau was referred to as cytosolic tau, amorphous tau, and sedimentable cytosolic abnormally hyperphosphorylated tau [ 1920314143 - 47 ].
Four of these missense mutations, GV, PL, VM, and RW, which have been most studied to date, make tau a preferable substrate for abnormal hyperphosphorylation in vitro [ 21 ].
To date, the only established function of tau, a phosphoprotein, is the promotion of the assembly of tubulin into microtubules and stabilization of their structure [ 3 ]. These data indicate that the mis-localisation of fyn caused by truncated tau rescued amyloid-induced phenotypes.
To date, not only in AD but also in every known human tauopathy, the tau pathology is made up of the abnormally hyperphosphorylated protein. Some of the tau in AD brain is truncated which also promotes its self-assembly.
In Alzheimer disease AD and a family of related neurodegenerative diseases, called tauopathies, tau protein is abnormally hyperphosphorylated and aggregated into bundles of filaments [ 4 ]. This article discusses the relationship between normal and pathological taus found in AD and related tauopathies.
To date, in aged and in cognitively impaired animals the neurofibrillary degeneration of abnormally hyperphosphorylated tau has been found only sparsely.
Thus, understan ding the etiopathogenesis of this pivotal and hallmark lesion of AD and related tauopathies is critical to developing rational therapeutic treatments of these human CNS diseases.Of particular interest, a mouse model over-expressing wild-type human tau also develops neurodegenerative features with old age, including cell death and abnormal nuclei (Andorfer et al.
). Therefore, mechanisms leading to the buildup of these proteins in the human brain have become the focus in research on the pathology of AD.
High intensity scans of western blots of control and Alzheimer’s disease (AD) post-mortem human brain tissue from Fig. 4 reveal weak detection of tau phosphorylated at (a) S (CP13) and (b) S/S (PHF-1) in control brain tissue, whereas the signal in AD brain is overexposed when shown at this intensity.
The molecular weight marker (50 kDa) is. In order to understand the roles of individual MARK isoforms in phosphorylation of tau at Ser in cells and in postmortem human brains, we first validated the isoform-specificity of a panel of antibodies by in situ PLA in rhTau3T3 cells transfected with.
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.
In Alzheimer’s disease (AD) patient brains, PP2A activities were decreased (Gong et al.,Gong et al., ). In vitro analysis of the dephosphorylation ability of different phosphatases toward tau showed that PP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains (Liu et al., ).
As an alternative, recombinant tau expression for all six isoforms in Escherichia coli was reported by Goedert and Jakes, [6 Goedert, M.; Jakes, R.
Expression of Separate Isoforms of Human Tau Protein: Correlation with the Tau Pattern in Brain and Effects on Tubulin Polymerization.Download