Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model
The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but i...
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MDPI AG
2022-07-01
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| author | Alexandra Bluhm Sarah Schrempel Stephan Schilling Stephan von Hörsten Anja Schulze Steffen Roßner Maike Hartlage-Rübsamen |
| author_facet | Alexandra Bluhm Sarah Schrempel Stephan Schilling Stephan von Hörsten Anja Schulze Steffen Roßner Maike Hartlage-Rübsamen |
| author_sort | Alexandra Bluhm |
| collection | DOAJ |
| description | The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead co-exist and interact with each other. Here, we investigated the presence of a newly identified, pyroglutamate79-modified α-synuclein variant (pGlu79-aSyn)—along with the enzyme matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation—in AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue. Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we demonstrate an association of pGlu79-aSyn, MMP-3 and QC with β-amyloid plaques. In addition, pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can be generated extracellularly or within reactive astrocytes, accumulates in proximity to β-amyloid plaques and induces an astrocytic protein unfolding mechanism involving HSP27. |
| first_indexed | 2024-03-09T10:22:01Z |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T10:22:01Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-2cf6a5bc4a9446cd8abe2fdaaaa8d0902023-12-01T21:56:44ZengMDPI AGBiomolecules2218-273X2022-07-01127100610.3390/biom12071006Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse ModelAlexandra Bluhm0Sarah Schrempel1Stephan Schilling2Stephan von Hörsten3Anja Schulze4Steffen Roßner5Maike Hartlage-Rübsamen6Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, GermanyPaul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, GermanyFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle (Saale), GermanyDepartment for Experimental Therapy, University Clinics Erlangen and Preclinical Experimental Center, University of Erlangen-Nuremberg, 91054 Erlangen, GermanyFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle (Saale), GermanyPaul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, GermanyPaul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, GermanyThe deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead co-exist and interact with each other. Here, we investigated the presence of a newly identified, pyroglutamate79-modified α-synuclein variant (pGlu79-aSyn)—along with the enzyme matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation—in AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue. Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we demonstrate an association of pGlu79-aSyn, MMP-3 and QC with β-amyloid plaques. In addition, pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can be generated extracellularly or within reactive astrocytes, accumulates in proximity to β-amyloid plaques and induces an astrocytic protein unfolding mechanism involving HSP27.https://www.mdpi.com/2218-273X/12/7/1006Alzheimer’s diseaseβ-amyloidα-synucleinmatrix metalloproteinase-3glutaminyl cyclaseheat shock protein 27 |
| spellingShingle | Alexandra Bluhm Sarah Schrempel Stephan Schilling Stephan von Hörsten Anja Schulze Steffen Roßner Maike Hartlage-Rübsamen Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model Biomolecules Alzheimer’s disease β-amyloid α-synuclein matrix metalloproteinase-3 glutaminyl cyclase heat shock protein 27 |
| title | Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model |
| title_full | Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model |
| title_fullStr | Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model |
| title_full_unstemmed | Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model |
| title_short | Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model |
| title_sort | immunohistochemical demonstration of the pglu79 α synuclein fragment in alzheimer s disease and its tg2576 mouse model |
| topic | Alzheimer’s disease β-amyloid α-synuclein matrix metalloproteinase-3 glutaminyl cyclase heat shock protein 27 |
| url | https://www.mdpi.com/2218-273X/12/7/1006 |
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