p(HBP:"Tau C3")
Furthermore, active caspase co-localizes to NFTs (58), and caspase-cleaved tau is found in AD-affected brain regions, particularly in neurons displaying tangle pathology (59, 60). This includes tau cleaved by caspase-6 in the C-terminus (58–60) as well as in the N-terminus (24). TauC3 is present in AD brain – in neurons and co-localized with NFTs – and inversely correlates with cognitive function (55, 60, 61). PubMed:24027553
This is supported by evidence that full-length tau, which has a lower propensity for aggregating, is cleared by the proteasome while caspase- cleaved tau, which is more aggregate prone, goes through autophagy (72). Also, aggregated tau can be cleared by inducing autophagy (70, 96). PubMed:24027553
Finally, caspase-3 cleaved tau has a shorter half-life than full-length tau and is preferentially degraded by autophagy (72). PubMed:24027553
Furthermore, expressing a cleavage resistant form of tau (D421E) protects cells from apoptotic cell death (22). Another potential mechanism of inducing caspase-3 cleavage of tau is the presence of Aβ peptides. TauC3 is formed in primary cortical neurons after treatment with Aβ (23). PubMed:24027553
There may be reciprocity with the apoptosis pathway as activating caspase-3 by inducing apoptosis in cortical neuronal culture led to tau cleavage (22), and selectively expressing tauC3 led to apoptosis in NT2 and COS cells (21). This might represent a feed-forward loop of neurotoxicity. PubMed:24027553
Caspase cleavage of tau may play a role in stimulating the tau aggregation seen in AD. Indeed, in vitro polymerization assays demonstrate that caspase-cleaved tau has a greater propensity to aggregate compared to full-length tau (23, 55). PubMed:24027553
As expected, we observed a significant impairment of mitochondrial distribution with overexpression of all three tau constructs (p < 0.0001, Wilcoxon test for GFP control versus 4R-tau, GFP versus tauC3, and GFP versus K18ΔK280) (Fig. 5). PubMed:25374103
Taken together, these data indicate that tau-overexpression leads to abnormal mitochondrial trafficking that can be rescued by CHIP-co-expression PubMed:25374103
CHIP interacts more strongly with tauΔC than full-length tau [18], suggesting it is involved in caspase cleaved tau degradation PubMed:25374103
Recent data suggest that caspases are involved in the accumulation of tau pathology [10, 25, 26], and reductions in CHIP have been shown to cause caspase activation and increased caspase-cleaved tau levels [19]. PubMed:25374103
These results indicate that CHIP is involved in degradation of caspases and caspase-cleaved tau. PubMed:25374103
Densitometry analysis of total tau levels of H4- cell lysates on SDS-PAGE showed a 2.0 to 2.5 fold lower levels of tau (4R-tau, tauC3, and K18ΔK280) with co-expression with CHIP, respectively (Fig. 1). PubMed:25374103
Indeed, the co-expression of CHIP caused a significant decrease tauC3 in vitro (Fig. 4). PubMed:25374103
Tau overexpression increased active caspase 3 levels, and co-expression of CHIP reduced cleaved caspase 3 levels compared to tau expression alone (Fig. 3). PubMed:25374103
In CHIP knockout mice, Caspase 3 activation is increased and caspase-cleaved tau levels are increased [17]. PubMed:25374103
For example, as discussed above, certain modified forms of tau, such as caspase-cleaved tau, have a stronger tendency to aggregate. As tau begins to assemble into oligomers, it may become increasingly undesirable as a proteasomal substrate. These low-order, soluble oligomers may be preferentially degraded by autophagy. PubMed:24027553
There may be reciprocity with the apoptosis pathway as activating caspase-3 by inducing apoptosis in cortical neuronal culture led to tau cleavage (22), and selectively expressing tauC3 led to apoptosis in NT2 and COS cells (21). This might represent a feed-forward loop of neurotoxicity. PubMed:24027553
Caspase cleavage of tau may play a role in stimulating the tau aggregation seen in AD. Indeed, in vitro polymerization assays demonstrate that caspase-cleaved tau has a greater propensity to aggregate compared to full-length tau (23, 55). PubMed:24027553
Furthermore, active caspase co-localizes to NFTs (58), and caspase-cleaved tau is found in AD-affected brain regions, particularly in neurons displaying tangle pathology (59, 60). This includes tau cleaved by caspase-6 in the C-terminus (58–60) as well as in the N-terminus (24). TauC3 is present in AD brain – in neurons and co-localized with NFTs – and inversely correlates with cognitive function (55, 60, 61). PubMed:24027553
Toxicity assays revealed that neither CHIP nor any of the tau constructs caused cell death compared to the control GFP vector (Supplementary Fig. 1). PubMed:25374103
Recent data suggest that caspases are involved in the accumulation of tau pathology [10, 25, 26], and reductions in CHIP have been shown to cause caspase activation and increased caspase-cleaved tau levels [19]. PubMed:25374103
Tau overexpression increased active caspase 3 levels, and co-expression of CHIP reduced cleaved caspase 3 levels compared to tau expression alone (Fig. 3). PubMed:25374103
As expected, we observed a significant impairment of mitochondrial distribution with overexpression of all three tau constructs (p < 0.0001, Wilcoxon test for GFP control versus 4R-tau, GFP versus tauC3, and GFP versus K18ΔK280) (Fig. 5). PubMed:25374103
Taken together, these data indicate that tau-overexpression leads to abnormal mitochondrial trafficking that can be rescued by CHIP-co-expression PubMed:25374103
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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.