Limits...
The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes.

Lasagna-Reeves CA, Sengupta U, Castillo-Carranza D, Gerson JE, Guerrero-Munoz M, Troncoso JC, Jackson GR, Kayed R - Acta Neuropathol Commun (2014)

Bottom Line: Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood.Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate.Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type.

View Article: PubMed Central - PubMed

Affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA. rakayed@utmb.edu.

ABSTRACT
Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

Show MeSH

Related in: MedlinePlus

Tau APFs are not phosphorylated at Ser202/Thr205. (a) Tau APFs were examined after double immunofluorescence labeling using Tau-5 (green) and αAPF (red) in DLB and PSP sections. (b) Double labeling with AT8 (green) and αAPF (red) revealed lack of colocalization in all of cases, indicating that tau APFs are not largely phosphorylated at Ser202/Thr205. Scale bar, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4231072&req=5

Fig3: Tau APFs are not phosphorylated at Ser202/Thr205. (a) Tau APFs were examined after double immunofluorescence labeling using Tau-5 (green) and αAPF (red) in DLB and PSP sections. (b) Double labeling with AT8 (green) and αAPF (red) revealed lack of colocalization in all of cases, indicating that tau APFs are not largely phosphorylated at Ser202/Thr205. Scale bar, 10 μm.

Mentions: To confirm that the APFs detected in DLB and PSP samples were indeed tau APFs, we performed double immunofluorescence labeling using the αAPF antibody and the tau-specific Tau-5 antibody. High levels of colocalization were seen in sections colabeled with αAPF and Tau-5, which recognizes all forms of tau (Figure 3a and Additional file 2: Figure S2a). However, in double labeling using AT8, which recognizes tau phosphorylated at Ser202/Thr205 (found in NFTs) [43], no colocalization was for AT8 and αAPF (Figure 3b and Additional file 2: Figure S2b). Therefore, it is likely that tau APFs are not highly phosphorylated at epitopes Ser202/Thr205 and arise from a different form of tau than that found in NFTs.Figure 3


The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes.

Lasagna-Reeves CA, Sengupta U, Castillo-Carranza D, Gerson JE, Guerrero-Munoz M, Troncoso JC, Jackson GR, Kayed R - Acta Neuropathol Commun (2014)

Tau APFs are not phosphorylated at Ser202/Thr205. (a) Tau APFs were examined after double immunofluorescence labeling using Tau-5 (green) and αAPF (red) in DLB and PSP sections. (b) Double labeling with AT8 (green) and αAPF (red) revealed lack of colocalization in all of cases, indicating that tau APFs are not largely phosphorylated at Ser202/Thr205. Scale bar, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4231072&req=5

Fig3: Tau APFs are not phosphorylated at Ser202/Thr205. (a) Tau APFs were examined after double immunofluorescence labeling using Tau-5 (green) and αAPF (red) in DLB and PSP sections. (b) Double labeling with AT8 (green) and αAPF (red) revealed lack of colocalization in all of cases, indicating that tau APFs are not largely phosphorylated at Ser202/Thr205. Scale bar, 10 μm.
Mentions: To confirm that the APFs detected in DLB and PSP samples were indeed tau APFs, we performed double immunofluorescence labeling using the αAPF antibody and the tau-specific Tau-5 antibody. High levels of colocalization were seen in sections colabeled with αAPF and Tau-5, which recognizes all forms of tau (Figure 3a and Additional file 2: Figure S2a). However, in double labeling using AT8, which recognizes tau phosphorylated at Ser202/Thr205 (found in NFTs) [43], no colocalization was for AT8 and αAPF (Figure 3b and Additional file 2: Figure S2b). Therefore, it is likely that tau APFs are not highly phosphorylated at epitopes Ser202/Thr205 and arise from a different form of tau than that found in NFTs.Figure 3

Bottom Line: Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood.Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate.Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type.

View Article: PubMed Central - PubMed

Affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA. rakayed@utmb.edu.

ABSTRACT
Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

Show MeSH
Related in: MedlinePlus