bp(GO:"neurofibrillary tangle assembly")

Entity

Name

neurofibrillary tangle assembly

Namespace

go

Namespace Version

20181221

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/73688d6dc24e309fca59a1340dc9ee971e9f3baa/external/go-names.belns

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142] PubMed:21214928

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009) PubMed:22122372

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

HSPGs are ubiquitously expressed in many cell types including neurons, and have been previously associated with dense core plaques, cerebrovascular amyloid, and NFT formation (van Horssen et al., 2001) PubMed:28420982

Two hexapeptide motifs at the beginning of R2 and R3 promote paired helical filament (PHF) aggregation by inducing β-structure. PubMed:17493042

Two hexapeptide motifs at the beginning of R2 and R3 promote paired helical filament (PHF) aggregation by inducing β-structure. PubMed:17493042

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

As noticed earler, it is difficult to obtain PHFs from constructs containing domains outside the repeats or the second repeat, at least under conditions where assembly is driven by high ionic strength and high protein concentration [5,26]. This would suggest that some non-repeat domains of tau prevent PHF formation. The same tendency is observed here again, but low we find that the inhibition can be easily overcome by RNA in most cases. Since dimers are building blocks of PHFs, the extra repeat (no. 2) effectively acted as a PHF inhibitor [22]. However, this inhibition can be overcome by tRNA. PubMed:8985176

Figure 5 shows the presence of fibrillar polymers when the Hsp90 was mixed with tau protein. These filaments are similar to tau aggregates assembled in the presence of quinones [19] such as juglone, used here as a positive control (Fig. 5C). No filaments were observed in control samples of tau2R alone (Fig. 5A) or Hsp90 alone (data not shown). PubMed:19363271

Figure 5 shows the presence of fibrillar polymers when the Hsp90 was mixed with tau protein. These filaments are similar to tau aggregates assembled in the presence of quinones [19] such as juglone, used here as a positive control (Fig. 5C). No filaments were observed in control samples of tau2R alone (Fig. 5A) or Hsp90 alone (data not shown). PubMed:19363271

CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA. PubMed:23531502

Glycation by AGE (Advanced Glycation End products) decreases MT binding, promotes aggregation, activates RAGE PubMed:8063802

We found that CA (lane 4) and EC (lane 6) substantially prevented the H2O2 induced formation of the high molecular weight species. PubMed:23531502

CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA. PubMed:23531502

In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. PubMed:16816118

In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. PubMed:16816118

However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15]. PubMed:26655600

The results show that 4R2N and 3R2N Tau increase their aggregation extent with glycation while 3R1N decreases aggregation properties with glycation PubMed:26655600

Despite 4R1N having no significant change, the same modified 4R2N Tau promotes its aggregation significantly (Fig. 6A, C, E). PubMed:26655600

The results show that 4R2N and 3R2N Tau increase their aggregation extent with glycation while 3R1N decreases aggregation properties with glycation PubMed:26655600

Glycation and phosphorylation of both 4R1Nand 4R0NTau reduce its aggregation. PubMed:26655600

Glycation and phosphorylation of both 4R1Nand 4R0NTau reduce its aggregation. PubMed:26655600

Glycation and phosphorylation of both 4R1Nand 4R0NTau reduce its aggregation. PubMed:26655600

Glycation and phosphorylation of both 4R1Nand 4R0NTau reduce its aggregation. PubMed:26655600

The results show that 4R2N and 3R2N Tau increase their aggregation extent with glycation while 3R1N decreases aggregation properties with glycation PubMed:26655600

Despite 4R1N having no significant change, the same modified 4R2N Tau promotes its aggregation significantly (Fig. 6A, C, E). PubMed:26655600

CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA. PubMed:23531502

Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. PubMed:17050703

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

HSPGs are ubiquitously expressed in many cell types including neurons, and have been previously associated with dense core plaques, cerebrovascular amyloid, and NFT formation (van Horssen et al., 2001) PubMed:28420982

Figure 5 shows the presence of fibrillar polymers when the Hsp90 was mixed with tau protein. These filaments are similar to tau aggregates assembled in the presence of quinones [19] such as juglone, used here as a positive control (Fig. 5C). No filaments were observed in control samples of tau2R alone (Fig. 5A) or Hsp90 alone (data not shown). PubMed:19363271

We found that CA (lane 4) and EC (lane 6) substantially prevented the H2O2 induced formation of the high molecular weight species. PubMed:23531502

However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15]. PubMed:26655600

Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. PubMed:17050703

In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. PubMed:16816118