Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes
Abstract The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer’s disease (AD...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-04-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-00934-5 |
| _version_ | 1818274979542728704 |
|---|---|
| author | Sandra O. Tomé Rik Vandenberghe Simona Ospitalieri Evelien Van Schoor Thomas Tousseyn Markus Otto Christine A. F. von Arnim Dietmar Rudolf Thal |
| author_facet | Sandra O. Tomé Rik Vandenberghe Simona Ospitalieri Evelien Van Schoor Thomas Tousseyn Markus Otto Christine A. F. von Arnim Dietmar Rudolf Thal |
| author_sort | Sandra O. Tomé |
| collection | DOAJ |
| description | Abstract The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer’s disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP + CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP + CTF cases, 63,6% of ADTDP + FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP + FL, in 16,6% of the ADTDP + CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP + CTF and ADTDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP + FL cases. |
| first_indexed | 2024-12-12T22:22:28Z |
| format | Article |
| id | doaj.art-b65a58e10bb441299d9e03fef187ab0c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-12T22:22:28Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-b65a58e10bb441299d9e03fef187ab0c2022-12-22T00:09:52ZengBMCActa Neuropathologica Communications2051-59602020-04-018112210.1186/s40478-020-00934-5Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypesSandra O. Tomé0Rik Vandenberghe1Simona Ospitalieri2Evelien Van Schoor3Thomas Tousseyn4Markus Otto5Christine A. F. von Arnim6Dietmar Rudolf Thal7Department of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-LeuvenDepartment of Neurosciences – Laboratory of Cognitive Neurology, KU- LeuvenDepartment of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-LeuvenDepartment of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-LeuvenDepartment of Imaging and Pathology - Translational Cell and Tissue Research Unit, KU-LeuvenDepartment of Neurology, Ulm UniversityDepartment of Neurology, Ulm UniversityDepartment of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-LeuvenAbstract The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer’s disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP + CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP + CTF cases, 63,6% of ADTDP + FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP + FL, in 16,6% of the ADTDP + CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP + CTF and ADTDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP + FL cases.http://link.springer.com/article/10.1186/s40478-020-00934-5Alzheimer’s disease (AD)Frontotemporal lobar degeneration (FTLD)TDP-43Protein aggregationPhosphorylation |
| spellingShingle | Sandra O. Tomé Rik Vandenberghe Simona Ospitalieri Evelien Van Schoor Thomas Tousseyn Markus Otto Christine A. F. von Arnim Dietmar Rudolf Thal Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes Acta Neuropathologica Communications Alzheimer’s disease (AD) Frontotemporal lobar degeneration (FTLD) TDP-43 Protein aggregation Phosphorylation |
| title | Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes |
| title_full | Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes |
| title_fullStr | Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes |
| title_full_unstemmed | Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes |
| title_short | Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes |
| title_sort | distinct molecular patterns of tdp 43 pathology in alzheimer s disease relationship with clinical phenotypes |
| topic | Alzheimer’s disease (AD) Frontotemporal lobar degeneration (FTLD) TDP-43 Protein aggregation Phosphorylation |
| url | http://link.springer.com/article/10.1186/s40478-020-00934-5 |
| work_keys_str_mv | AT sandraotome distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT rikvandenberghe distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT simonaospitalieri distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT evelienvanschoor distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT thomastousseyn distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT markusotto distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT christineafvonarnim distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes AT dietmarrudolfthal distinctmolecularpatternsoftdp43pathologyinalzheimersdiseaserelationshipwithclinicalphenotypes |