p(HBP:"phosphatase-activating domain")

Entity

Name

phosphatase-activating domain

Namespace

HBP

Namespace Version

20181119

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/90e1cb9e5e882703380c9db8d4915ac6f3cba137/export/hbp-names.belns

Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). PubMed:26671985

Aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. PubMed:27574109

Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event. PubMed:27260838

Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event. PubMed:27260838

Apparent ThR-positive ghost tangles (i.e., without nuclei (Braak et al., 1994)) are no longer labeled by TNT1 or TNT2, which confirms that PAD exposure is lost in the latest stages of NFT evolution. PubMed:27260838

Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. PubMed:27373205

Apparent ThR-positive ghost tangles (i.e., without nuclei (Braak et al., 1994)) are no longer labeled by TNT1 or TNT2, which confirms that PAD exposure is lost in the latest stages of NFT evolution. PubMed:27260838

Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). PubMed:26671985

Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). PubMed:26671985

We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. PubMed:26671985

We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. PubMed:26671985

Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event. PubMed:27260838

Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event. PubMed:27260838

Aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. PubMed:27574109

Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. PubMed:27373205

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277