p(MGI:Mapt)
We found that WT tau was taken up and efficiently degraded by LE (Fig. 2c,d) PubMed:29024336
In contrast, once the first N-terminal insert is lost (in 0N3R tau), we observed a very pronounced decrease in tau uptake (Fig. 5b,c) PubMed:29024336
Absence of the second N-terminal insert (in 1N3R tau) did not reduce CMA of tau, but instead this isoform displayed faster internalization (lower binding because of more efficient uptake) (Fig. 5b,c) PubMed:29024336
Absence of the second N-terminal insert also significantly reduced e-MI of tau (Fig. 5e,f) PubMed:29024336
Analysis of their uptake by isolated CMA-active lysosomes revealed that 2N3R tau behaved similarly to 2N4R tau (which we have used in the rest of the study as control) PubMed:29024336
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336
Taken together, our in vitro and cell-based studies argue that these two point mutations, A152T and P301L, reduce the normal degradation of tau by CMA, although the P301L mutation has a more pronounced inhibitory effect PubMed:29024336
Our previous studies and data presented in this work support substantial contribution of CMA to the degradation of wild-type unmodified tau (Wang et al., 2009) PubMed:29024336
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336
Interestingly, although judging by the studies in intact cells the contribution of e-MI to tau degradation is small (Fig. 2a), our in vitro studies with isolated LE revealed a high efficiency for e-MI of tau (Fig. 2c) PubMed:29024336
Previous studies have demonstrated that oxidized proteins accumulate inside multivesicular bodies (Cannizzo et al., 2012), suggesting that oxidation may be a prerequisite to complete internalization of tau by e-MI, and that the LE environment may contribute to that modification PubMed:29024336
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336
Macroautophagy blockage resulted in preferential accumulation of A152T, but not WT and P301L tau (Fig. 2e,f) PubMed:29024336
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336
An increase in overall tau levels has been observed in brains from patients bearing either P301L or A152T mutation on tau (Torres et al., 1998) PubMed:29024336
Taken together, our in vitro and cell-based studies argue that these two point mutations, A152T and P301L, reduce the normal degradation of tau by CMA, although the P301L mutation has a more pronounced inhibitory effect PubMed:29024336
In summary, when comparing the pathogenic tau mutation P301L with the risk-associated mutation A152T, we found that both reduced normal turnover of tau by autophagy, but that the effect of the P301L mutation was more pronounced (summarized in Fig. 2g and Fig. S6, Supporting information) PubMed:29024336
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336
An increase in overall tau levels has been observed in brains from patients bearing either P301L or A152T mutation on tau (Torres et al., 1998) PubMed:29024336
In contrast, the P301L mutation severely impaired lysosomal uptake of tau by CMA, resulting in a sixfold decrease in degradation when compared to WT tau protein (Fig. 1c,d) PubMed:29024336
Taken together, our in vitro and cell-based studies argue that these two point mutations, A152T and P301L, reduce the normal degradation of tau by CMA, although the P301L mutation has a more pronounced inhibitory effect PubMed:29024336
In summary, when comparing the pathogenic tau mutation P301L with the risk-associated mutation A152T, we found that both reduced normal turnover of tau by autophagy, but that the effect of the P301L mutation was more pronounced (summarized in Fig. 2g and Fig. S6, Supporting information) PubMed:29024336
Tau-A152T displayed very similar degradation dynamics, although this mutation slightly reduced tau’s rates of lysosomal degradation (20% inhibition) when compared with WT tau (Fig. 1a,b). PubMed:29024336
In the controls and the antiaggregant TauRDΔKPP slices there was a uniform axonal distribution of Tau in the hippocampus (Fig. 5, A1 and 2) PubMed:29202785
Surprisingly, there was an ~80% increase in the endogenous mouse Tau level in slices obtained from pups expressing anti-aggregant TauRDΔKPP (Fig. 5b lane 2 and 5c bar 2), compared with age matched non-transgenic controls and pro-aggregant TauRDΔK (Fig. 5b lane 1 and 3; and 5c lane 1 and 3) PubMed:29202785
In spite of this increase, there was little mislocalization of Tau (endogenous or exogenous) into the somatodendritic compartment in the anti-aggregant TauRDΔKPP (Fig. 5, A2) PubMed:29202785
From DIV15 until DIV30 the anti-aggregant slices were treated with DOX to switch off the expression of the anti-aggregant Tau. This lead to a strong reduction (~70%) of the endogenous mouse Tau (Fig. 10c, lane3) PubMed:29202785
The pro-aggregant TauRDΔK slices showed intense mislocalization of Tau in the somato-dendritic compartment, the most affected being the CA3 pyramidal neurons (Fig. 5, A3) PubMed:29202785
By contrast, pro-aggregant TauRDΔK slices showed no overall increase in endogenous mouse Tau (rather a 20% decrease), yet pronounced mislocalization (Fig. 5, A3). PubMed:29202785
By contrast, pro-aggregant TauRDΔK slices showed no overall increase in endogenous mouse Tau (rather a 20% decrease), yet pronounced mislocalization (Fig. 5, A3). PubMed:29202785
In the insoluble fraction, phospho- and total tau species were all reduced in the TFEB mice, as demonstrated by Western blot PubMed:30108137
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
The 40E8, 4E4, and p396 antibodies also reduced neuronal tau uptake by 40% to 80%, despite their low-immunodepletion efficiency (Figure 2). This finding suggests that they interacted with tau species that are prone to cellular uptake, which account for only a small fraction of all soluble tau species in the brain extract. Notably, Tau46 had little effect on tau uptake (Figure 2, B and C). PubMed:28408124
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
The 40E8, 4E4, and p396 antibodies also reduced neuronal tau uptake by 40% to 80%, despite their low-immunodepletion efficiency (Figure 2). This finding suggests that they interacted with tau species that are prone to cellular uptake, which account for only a small fraction of all soluble tau species in the brain extract. Notably, Tau46 had little effect on tau uptake (Figure 2, B and C). PubMed:28408124
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
Confocal FRET image analysis showed robust tau aggregation in primary neurons treated with control IgG-immunodepleted rTg4510 brain extracts (Figure 2, B and C).The 6C5 antibody most successfully reduced tau uptake by immunodepletion (>90% reduction), and Tau13 and HT7 showed intermediate effects (approximately 60% reductions) (Figure 2, B and C) PubMed:28408124
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
Confocal FRET image analysis showed robust tau aggregation in primary neurons treated with control IgG-immunodepleted rTg4510 brain extracts (Figure 2, B and C).The 6C5 antibody most successfully reduced tau uptake by immunodepletion (>90% reduction), and Tau13 and HT7 showed intermediate effects (approximately 60% reductions) (Figure 2, B and C) PubMed:28408124
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
Confocal FRET image analysis showed robust tau aggregation in primary neurons treated with control IgG-immunodepleted rTg4510 brain extracts (Figure 2, B and C).The 6C5 antibody most successfully reduced tau uptake by immunodepletion (>90% reduction), and Tau13 and HT7 showed intermediate effects (approximately 60% reductions) (Figure 2, B and C) PubMed:28408124
Among the seven antibodies, Tau13 and 6C5 most efficiently removed tau (>85% reduction) from rTg4510 brain extracts on immunodepletion (Figure 2A). HT7 showed an intermediate effect (72% reduction), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (5.6%, 16.6%, 8.4%, and 18% reductions, respectively) (Figure 2A). PubMed:28408124
The 40E8, 4E4, and p396 antibodies also reduced neuronal tau uptake by 40% to 80%, despite their low-immunodepletion efficiency (Figure 2). This finding suggests that they interacted with tau species that are prone to cellular uptake, which account for only a small fraction of all soluble tau species in the brain extract. Notably, Tau46 had little effect on tau uptake (Figure 2, B and C). PubMed:28408124
A rapid but transient increase was found in the amount of fyn detected in DRMs on ADDL exposure for 2 min that was partially reduced after 10 min exposure. Mirroring the movement of fyn into the DRM, tau content of DRMs increased in response to ADDLs. To further test a putative association between fyn and tau levels in DRMs, we treated cells with 2-bromopalmitate, an inhibitor of protein palmitoylation, which is required for fyn’s localization in DRMs. This treatment resulted in a progressive reduction in both fyn and tau in DRMs, demonstrating that the association of tau with DRMs may be directly regulated by fyn (Supplemental Fig. 2). PubMed:18096814
A rapid but transient increase was found in the amount of fyn detected in DRMs on ADDL exposure for 2 min that was partially reduced after 10 min exposure. Mirroring the movement of fyn into the DRM, tau content of DRMs increased in response to ADDLs. To further test a putative association between fyn and tau levels in DRMs, we treated cells with 2-bromopalmitate, an inhibitor of protein palmitoylation, which is required for fyn’s localization in DRMs. This treatment resulted in a progressive reduction in both fyn and tau in DRMs, demonstrating that the association of tau with DRMs may be directly regulated by fyn (Supplemental Fig. 2). PubMed:18096814
A rapid but transient increase was found in the amount of fyn detected in DRMs on ADDL exposure for 2 min that was partially reduced after 10 min exposure. Mirroring the movement of fyn into the DRM, tau content of DRMs increased in response to ADDLs. To further test a putative association between fyn and tau levels in DRMs, we treated cells with 2-bromopalmitate, an inhibitor of protein palmitoylation, which is required for fyn’s localization in DRMs. This treatment resulted in a progressive reduction in both fyn and tau in DRMs, demonstrating that the association of tau with DRMs may be directly regulated by fyn (Supplemental Fig. 2). PubMed:18096814
Direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death. DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice. PubMed:25995053
Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. PubMed:29221819
It was possible to find nitrated Tyr 488 (numbers refer to mouse tau P10637 in the Swiss-Prot/ThEMBL data bank) which corresponds to Tyr 507 in rat tau (Table 1) in accordance with the data reported above for tau in PC12 cells. PubMed:17768677
Interestingly, Syk upregulation in SH-SY5Y cells leads to a significant increase (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells. Total tau levels are also significantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001). PubMed:28877763
This revealed a significant increase of monomeric Tau and oligomeric Tau in AAV– Otub1-injected mice compared with AAV–GFP-injected mice (Fig. 7c). PubMed:28083634
In the presence of any of the tau proteins, we found some sequestration of the probe in the multivesicular bodies, albeit significantly less in cells expressing the WT and A152T protein PubMed:29024336
This suggests that the expression of anti-aggregant TauRDΔKPP is needed for the increased proliferation of newborn neurons, and since these new born neurons need endogenous mouse Tau for their migration, differentiation, and maturation, there is enhanced expression of endogenous mouse Tau PubMed:29202785
This suggests that the expression of anti-aggregant TauRDΔKPP is needed for the increased proliferation of newborn neurons, and since these new born neurons need endogenous mouse Tau for their migration, differentiation, and maturation, there is enhanced expression of endogenous mouse Tau PubMed:29202785
This suggests that the expression of anti-aggregant TauRDΔKPP is needed for the increased proliferation of newborn neurons, and since these new born neurons need endogenous mouse Tau for their migration, differentiation, and maturation, there is enhanced expression of endogenous mouse Tau PubMed:29202785
However, genetically ablating endogenous mouse tau (microtubule associated protein tau, Mapt) reduces NFT pathology and neurodegeneration in tauNFT mice (tauNFT-Mapt0/0) (Wegmann et al., 2015) PubMed:30126037
However, genetically ablating endogenous mouse tau (microtubule associated protein tau, Mapt) reduces NFT pathology and neurodegeneration in tauNFT mice (tauNFT-Mapt0/0) (Wegmann et al., 2015) PubMed:30126037
The reduced tau pathology corresponded with 60% lower Cdkn2a expression (P = 0.0041, Figure 4a), decreased SASP (Figure S4) and decreased brain atrophy (tauNFT-Mapt0/0: 0.4058 ± 0.009 versus age-matched tauNFT Maptwt/wt: 0.3451 ± 0.0116; 17.5% difference, P = 0.0143, Figure 4b) PubMed:30126037
The reduced tau pathology corresponded with 60% lower Cdkn2a expression (P = 0.0041, Figure 4a), decreased SASP (Figure S4) and decreased brain atrophy (tauNFT-Mapt0/0: 0.4058 ± 0.009 versus age-matched tauNFT Maptwt/wt: 0.3451 ± 0.0116; 17.5% difference, P = 0.0143, Figure 4b) PubMed:30126037
The reduced tau pathology corresponded with 60% lower Cdkn2a expression (P = 0.0041, Figure 4a), decreased SASP (Figure S4) and decreased brain atrophy (tauNFT-Mapt0/0: 0.4058 ± 0.009 versus age-matched tauNFT Maptwt/wt: 0.3451 ± 0.0116; 17.5% difference, P = 0.0143, Figure 4b) PubMed:30126037
Confocal FRET image analysis showed robust tau aggregation in primary neurons treated with control IgG-immunodepleted rTg4510 brain extracts (Figure 2, B and C).The 6C5 antibody most successfully reduced tau uptake by immunodepletion (>90% reduction), and Tau13 and HT7 showed intermediate effects (approximately 60% reductions) (Figure 2, B and C) PubMed:28408124
A rapid but transient increase was found in the amount of fyn detected in DRMs on ADDL exposure for 2 min that was partially reduced after 10 min exposure. Mirroring the movement of fyn into the DRM, tau content of DRMs increased in response to ADDLs. To further test a putative association between fyn and tau levels in DRMs, we treated cells with 2-bromopalmitate, an inhibitor of protein palmitoylation, which is required for fyn’s localization in DRMs. This treatment resulted in a progressive reduction in both fyn and tau in DRMs, demonstrating that the association of tau with DRMs may be directly regulated by fyn (Supplemental Fig. 2). PubMed:18096814
First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates PubMed:26400044
Direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death. DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice. PubMed:25995053
Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. PubMed:29221819
Interestingly, Syk upregulation in SH-SY5Y cells leads to a significant increase (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells. Total tau levels are also significantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001). PubMed:28877763
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.