Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats
Abstract Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying me...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-59013-7 |
| _version_ | 1797209391679668224 |
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| author | Joseph M. Schrader Feng Xu Kevin J. Agostinucci Nicholas A. DaSilva William E. Van Nostrand |
| author_facet | Joseph M. Schrader Feng Xu Kevin J. Agostinucci Nicholas A. DaSilva William E. Van Nostrand |
| author_sort | Joseph M. Schrader |
| collection | DOAJ |
| description | Abstract Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses. |
| first_indexed | 2024-04-24T09:53:58Z |
| format | Article |
| id | doaj.art-16717bd1d98b4e0f84140aa0750b19aa |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T09:53:58Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-16717bd1d98b4e0f84140aa0750b19aa2024-04-14T11:12:15ZengNature PortfolioScientific Reports2045-23222024-04-0114111610.1038/s41598-024-59013-7Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI ratsJoseph M. Schrader0Feng Xu1Kevin J. Agostinucci2Nicholas A. DaSilva3William E. Van Nostrand4Department of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode IslandDepartment of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode IslandDepartment of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode IslandDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown UniversityDepartment of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode IslandAbstract Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.https://doi.org/10.1038/s41598-024-59013-7Cerebral amyloid angiopathyTransgenic ratsNeuroinflammationProteomicsBiomarkers |
| spellingShingle | Joseph M. Schrader Feng Xu Kevin J. Agostinucci Nicholas A. DaSilva William E. Van Nostrand Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats Scientific Reports Cerebral amyloid angiopathy Transgenic rats Neuroinflammation Proteomics Biomarkers |
| title | Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats |
| title_full | Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats |
| title_fullStr | Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats |
| title_full_unstemmed | Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats |
| title_short | Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats |
| title_sort | longitudinal markers of cerebral amyloid angiopathy and related inflammation in rtg di rats |
| topic | Cerebral amyloid angiopathy Transgenic rats Neuroinflammation Proteomics Biomarkers |
| url | https://doi.org/10.1038/s41598-024-59013-7 |
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