Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular resp...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/11/2982 |
| _version_ | 1797465884859564032 |
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| author | Xiaoyue Zhu Joseph M. Schrader Brandon A. Irizarry Steven O. Smith William E. Van Nostrand |
| author_facet | Xiaoyue Zhu Joseph M. Schrader Brandon A. Irizarry Steven O. Smith William E. Van Nostrand |
| author_sort | Xiaoyue Zhu |
| collection | DOAJ |
| description | Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of <i>PAI-1</i>, <i>MMP9</i>, <i>MMP12</i>, <i>CCL2</i>, and <i>C1r</i> in plaque-associated microglia, and <i>iNOS</i>, <i>GBP2</i>, and <i>C3D</i> in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including <i>IL1β</i> and <i>TNFα</i> in astrocytes, and microglial activation and <i>TGFβ1</i> in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment. |
| first_indexed | 2024-03-09T18:27:56Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T18:27:56Z |
| publishDate | 2022-11-01 |
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| spelling | doaj.art-f9e72154e7304181be9bc76737c5cf892023-11-24T07:47:11ZengMDPI AGBiomedicines2227-90592022-11-011011298210.3390/biomedicines10112982Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and MicrogliaXiaoyue Zhu0Joseph M. Schrader1Brandon A. Irizarry2Steven O. Smith3William E. Van Nostrand4George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USAGeorge and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USACenter for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USACenter for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USAGeorge and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USAFibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of <i>PAI-1</i>, <i>MMP9</i>, <i>MMP12</i>, <i>CCL2</i>, and <i>C1r</i> in plaque-associated microglia, and <i>iNOS</i>, <i>GBP2</i>, and <i>C3D</i> in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including <i>IL1β</i> and <i>TNFα</i> in astrocytes, and microglial activation and <i>TGFβ1</i> in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment.https://www.mdpi.com/2227-9059/10/11/2982amyloid β-proteinfibrilsastrocytesmicrogliaRNA sequencing |
| spellingShingle | Xiaoyue Zhu Joseph M. Schrader Brandon A. Irizarry Steven O. Smith William E. Van Nostrand Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia Biomedicines amyloid β-protein fibrils astrocytes microglia RNA sequencing |
| title | Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia |
| title_full | Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia |
| title_fullStr | Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia |
| title_full_unstemmed | Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia |
| title_short | Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia |
| title_sort | impact of aβ40 and aβ42 fibrils on the transcriptome of primary astrocytes and microglia |
| topic | amyloid β-protein fibrils astrocytes microglia RNA sequencing |
| url | https://www.mdpi.com/2227-9059/10/11/2982 |
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