Disease relevance of Mapt

• At the same time, Tau-P301LxGSK-3B mice have dramatic forebrain tauopathy, with "tangles in almost all neurons", although without hyper-phosphorylation of Tau. The data corroborate the hypothesis that GSK-3B is the missing link between the amyloid and tau-pathology, and position GSK-3B as prominent player in the pathogenesis in AD [1].
• Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration [2].
• Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) [2].
• The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates [3].
• Increased expression of beta-amyloid protein precursor and microtubule-associated protein tau during the differentiation of murine embryonal carcinoma cells [4].

Psychiatry related information on Mapt

• Numerous enzymes hyperphosphorylate Tau in vivo, leading to the formation of neurofibrillary tangles (NFTs) in the neurons of Alzheimer's disease (AD) [5].
• Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau [6].
• Individual Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration or Pick's disease [7].
• BAG-1 is highly expressed in neurons bearing Tau tangles in a mouse model of Alzheimer disease [8].

High impact information on Mapt

• Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A [9].
• However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau [10].
• In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3 beta, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases [11].
• Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3 beta activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease [11].
• Cdk5 purified from nervous tissue phosphorylates neuronal cytoskeletal proteins including neurofilament proteins and microtubule-associated protein tau in vitro [12].

Chemical compound and disease context of Mapt

• Expression of the genes encoding the beta/A4 amyloid protein precursor (APP) and microtubule-associated protein tau was studied in an embryonal carcinoma cell line (P19) that differentiates in vitro into cholinergic neurons after treatment with retinoic acid [4].
• The Tau antigen isolated from infected monkey cells was closely related but was not identical to the corresponding protein from human cells transformed by simian virus 40, as determined by two-dimensional mapping of their methionine-labeled tryptic peptides [13].
• The notion that taurine (Tau) has an osmoregulatory function in the mammalian brain has not been established, although it has been reported that the severity of hyponatremic edema is proportional to cerebral [Tau] [14].
• Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism [15].

Biological context of Mapt

• Stable transfection of a kinase-deficient ILK mutant (DN-ILK) resulted in aberrant tau phosphorylation in N1E-115 cells at sites recognized by the Tau-1 antibody that are identical to some of the phosphorylation sites in paired helical filaments, PHF-tau, in brains of patients with Alzheimer's disease [16].
• The same pathological alterations are known from AD patients or transgenic models overexpressing Tau or ApoE, however, these disturbances in axonal transport occur in the absence of any signs of concomitant Tau pathology [17].
• To investigate how Tau alterations provoke neurodegeneration we generated transgenic mice expressing human Tau with four tubulin-binding repeats (increased by FTDP-17 splice donor mutations) and three FTDP-17 missense mutations: G272V, P301L, and R406W [3].
• 4. These results imply a specific developmental regulation of mRNA translation of Tau, and indicate that, after the period of synapse formation is complete, and therefore axonal growth has finished (P20), only a limited number of new Tau molecules are synthesized [18].
• The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation [19].

Anatomical context of Mapt

• The microtubule-associated protein tau is essential for microtubule stabilization in neuronal axons [20].
• Moreover, correlation analyses involving Tau mice alone revealed linkage between poorer cognitive performance in all three water maze tasks and the number of neurofibrillary tangle (NFT)-containing neurons in neocortex and hippocampus [21].
• Ultrastructural analysis of mutant Tau-positive neurons revealed a pretangle appearance, with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD [3].
• 1. Tau, which is a microtubule-associated protein, with mRNA targeted to the axon and growth cone, is involved in axonal elongation [18].
• Here we demonstrate that Fyn binds to the cytoskeletal proteins Tau and alpha-Tubulin in oligodendrocytes [22].

Associations of Mapt with chemical compounds

• Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert [23].
• Using the high-resolution two-dimensional polyacrylamide gel electrophoresis system, we have resolved more than 60 distinct Tau isoforms in the adult mouse brain [24].
• The present data show that estradiol, in vivo, induces a transient activation of GSK3 in the adult female rat hippocampus, followed by a more sustained inhibition, as inferred from phosphorylation levels of Tau [25].
• Dyrk1A is found in sarkosyl-insoluble fractions which are enriched in phosphorylated tau in AD brains, thus suggesting a possible association of Dyrk1A with neurofibrillary tangle pathology [26].
• S3C-8 cells, overexpressing sema3C, were significantly more neuritogenic for CGN than poly l-lysine (PLL), a positive substrate for CGNs, as assessed by the measurement of the length of neurites and confirmed by Tau expression along the time of culture [27].
• On the other hand, the investigation of Tau protein at Ser-262 showed that interference in the insulin/PI3K and mTor signaling potentially influenced the Tau phosphorylation status at sites where only one of two enzymes (in this case PP2A) is involved in the regulation [28].

Physical interactions of Mapt

• This effect is likely to be caused by interference with the Fyn-Tau-microtubuli cascade rather than inactivation of the kinase, because Fyn bound to the mutant Tau retains activity [22].
• It has been suggested that the deleterious effects of the allele E4 of apolipoprotein E (apoE) in Alzheimer's disease (AD) are related to its inability to interact with the microtubule associated protein tau and to thereby prevent its hyperphosphorylation [29].

Regulatory relationships of Mapt

• Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models [30].
• Because ligation of the cell adhesion molecule F3 on oligodendrocytes leads to activation of Fyn kinase localized in rafts, these findings suggest that recruitment of Tau and Tubulin to activated Fyn kinase in rafts is an important step in the initiation of myelination [22].

Other interactions of Mapt

• ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3beta, which is a candidate kinase involved in PHF-tau formation [16].
• Disease-related modifications in tau affect the interaction between Fyn and Tau [31].
• Hippocampal samples taken from FAD mutant (I213T) PS1 knock-in mice contained hyperphosphorylated tau that reacted with various phosphodependent tau antibodies and with Alz50, which recognizes the conformational change of PHF tau [32].
• BDNF stimulation of neuronally differentiated P19 mouse embryonic carcinoma cells resulted in a rapid decrease in tau phosphorylation, at phosphorylation sites recognized by Tau 1, AT 8, AT 180 and p 262-Tau antibodies [20].
• APPsw transgenic mice bearing the "Swedish" amyloid precursor protein (APP) mutation and JNPL3 transgenic mice bearing the P301L (Tau) mutation were compared to control non-transgenic (NT) mice in an extensive behavioral test battery administered between 5 and 8.5 months of age [21].

Analytical, diagnostic and therapeutic context of Mapt

• Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones [33].
• Seven days after MDM injection, mice were killed and CNS tissue was collected and subjected to immunocytochemical and Western blot assays for leukocyte and neural antigens, GSK-3beta, and key kinase substrates such as beta-catenin and Tau [34].
• The 56,000-dalton Tau antigen appeared to share only two methionine-tryptic peptides with the large species of SV40 tumor antigen, as determined by ion-exchange and paper chromatographies [35].
• U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy [36].
• Hyperphosphorylation of Tau and filopodial retraction following microinjection of protein kinase C catalytic subunits [37].

References