Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease
Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has prov...
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| Format: | Article |
| Language: | English |
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BMC
2021-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01189-4 |
| _version_ | 1818624566475358208 |
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| author | Jonathan D. Cherry Camille D. Esnault Zachary H. Baucom Yorghos Tripodis Bertrand R. Huber Victor E. Alvarez Thor D. Stein Dennis W. Dickson Ann C. McKee |
| author_facet | Jonathan D. Cherry Camille D. Esnault Zachary H. Baucom Yorghos Tripodis Bertrand R. Huber Victor E. Alvarez Thor D. Stein Dennis W. Dickson Ann C. McKee |
| author_sort | Jonathan D. Cherry |
| collection | DOAJ |
| description | Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis. |
| first_indexed | 2024-12-16T18:59:00Z |
| format | Article |
| id | doaj.art-df47131b5ef34c2aa72f6431a93f45c1 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-16T18:59:00Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-df47131b5ef34c2aa72f6431a93f45c12022-12-21T22:20:27ZengBMCActa Neuropathologica Communications2051-59602021-05-019111710.1186/s40478-021-01189-4Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s diseaseJonathan D. Cherry0Camille D. Esnault1Zachary H. Baucom2Yorghos Tripodis3Bertrand R. Huber4Victor E. Alvarez5Thor D. Stein6Dennis W. Dickson7Ann C. McKee8VA Boston Healthcare SystemVA Boston Healthcare SystemDepartment of Biostatistics, Boston University School of Public HealthDepartment of Biostatistics, Boston University School of Public HealthVA Boston Healthcare SystemVA Boston Healthcare SystemVA Boston Healthcare SystemDepartment of Neuroscience, Mayo ClinicVA Boston Healthcare SystemAbstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.https://doi.org/10.1186/s40478-021-01189-4CTEADTau isoformsHippocampus3R4R |
| spellingShingle | Jonathan D. Cherry Camille D. Esnault Zachary H. Baucom Yorghos Tripodis Bertrand R. Huber Victor E. Alvarez Thor D. Stein Dennis W. Dickson Ann C. McKee Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease Acta Neuropathologica Communications CTE AD Tau isoforms Hippocampus 3R 4R |
| title | Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease |
| title_full | Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease |
| title_fullStr | Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease |
| title_full_unstemmed | Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease |
| title_short | Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease |
| title_sort | tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and alzheimer s disease |
| topic | CTE AD Tau isoforms Hippocampus 3R 4R |
| url | https://doi.org/10.1186/s40478-021-01189-4 |
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