path(MESH:"Supranuclear Palsy, Progressive")
Further highlighting the importance of the cholinergic system in the CNS, cholinergic neuronal loss, especially in the basal forebrain, occurs not only in AD, but also in Parkinson’s disease [190, 191], Down syndrome [192], amyotrophic lateral sclerosis [193, 194], progressive supranuclear palsy [195, 196], and olivopontocerebellar atrophy [197] PubMed:26813123
Consistent with the results from transgenic mice, CDKN2A was upregulated in PSP brains (P = 0.0415, Figure 4g) and expression correlated with NFT deposition, specifically in the parietal lobe (ANOVA, P = 0.0008; Kendall’s Tau rank correlation P = 0.059, Figure 4h) PubMed:30126037
Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
The onset of clinical symptoms in AD and PSP brains correlate with elevated levels of tau oligomer (Maeda et al., 2006, 2007; Patterson et al., 2011; Lasagna-Reeves et al., 2012b; Gerson et al., 2014a) PubMed:28420982
On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy). PubMed:26751493
There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD. PubMed:11089576
Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders. PubMed:22057784
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
Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300
Another MAPT polymorphism (A152T) was recently identified in patients diagnosed with progressive supranuclear palsy (PSP) (72–74). PubMed:29191965
In an analogy to the evolution of concepts in the ‘amyloid cascade hypothesis’, which proposes that soluble oligomers — rather than insoluble aggregates of amyloid peptides — are the causative agents of neurodegeneration in AD, recent studies have suggested tau oligomers to be the toxic species, and indeed levels of SDS-stable tau oligomers are increased in AD and PSP brains. PubMed:26631930
Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930
For instance, miR‑132, which is downregulated in PSP, reduces 4R tau expression in mouse neuroblastoma cells. PubMed:26631930
By contrast, acetylation of tau at Lys280 has been detected in AD and other tauopathies, including AGD, tangle-predominant senile dementia (TPSD), PiD, FTDP‑17 and PSP, and is pathological PubMed:26631930
Interestingly, the PSP-associated tau mutation A152T is localized far away from the repeat domain but still decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently PubMed:26631930
Intriguingly, SRSF2 levels are increased in the brains of individuals with PSP. PubMed:26631930
Further highlighting the importance of the cholinergic system in the CNS, cholinergic neuronal loss, especially in the basal forebrain, occurs not only in AD, but also in Parkinson’s disease [190, 191], Down syndrome [192], amyotrophic lateral sclerosis [193, 194], progressive supranuclear palsy [195, 196], and olivopontocerebellar atrophy [197] PubMed:26813123
Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991) PubMed:30126037
Consistent with the results from transgenic mice, CDKN2A was upregulated in PSP brains (P = 0.0415, Figure 4g) and expression correlated with NFT deposition, specifically in the parietal lobe (ANOVA, P = 0.0008; Kendall’s Tau rank correlation P = 0.059, Figure 4h) PubMed:30126037
The onset of clinical symptoms in AD and PSP brains correlate with elevated levels of tau oligomer (Maeda et al., 2006, 2007; Patterson et al., 2011; Lasagna-Reeves et al., 2012b; Gerson et al., 2014a) PubMed:28420982
On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy). PubMed:26751493
Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention. PubMed:12578227
Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention. PubMed:12578227
Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention. PubMed:12578227
Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention. PubMed:12578227
There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD. PubMed:11089576
Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders. PubMed:22057784
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
Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045
Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045
Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300
Another MAPT polymorphism (A152T) was recently identified in patients diagnosed with progressive supranuclear palsy (PSP) (72–74). PubMed:29191965
Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930
For instance, miR‑132, which is downregulated in PSP, reduces 4R tau expression in mouse neuroblastoma cells. PubMed:26631930
Intriguingly, SRSF2 levels are increased in the brains of individuals with PSP. PubMed:26631930
By contrast, acetylation of tau at Lys280 has been detected in AD and other tauopathies, including AGD, tangle-predominant senile dementia (TPSD), PiD, FTDP‑17 and PSP, and is pathological PubMed:26631930
Interestingly, the PSP-associated tau mutation A152T is localized far away from the repeat domain but still decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently PubMed:26631930
In an analogy to the evolution of concepts in the ‘amyloid cascade hypothesis’, which proposes that soluble oligomers — rather than insoluble aggregates of amyloid peptides — are the causative agents of neurodegeneration in AD, recent studies have suggested tau oligomers to be the toxic species, and indeed levels of SDS-stable tau oligomers are increased in AD and PSP brains. PubMed:26631930
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