Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model
Copyright © 2020 Meilandt et al. TREM2 is an Alzheimer’s disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) at ages ranging from 4 to 22 months. Microgliosi...
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| Format: | Article |
| Language: | English |
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Society for Neuroscience
2022
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| Online Access: | https://hdl.handle.net/1721.1/135187.2 |
| _version_ | 1811078137166954496 |
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| author | Meilandt, William J. Ngu, Hai Gogineni, Alvin Lalehzadeh, Guita Lee, Seung-Hye Srinivasan, Karpagam Imperio, Jose Wu, Tiffany Weber, Martin Kruse, Agatha J. Stark, Kimberly L. Chan, Pamela Kwong, Mandy Modrusan, Zora Friedman, Brad A. Elstrott, Justin Foreman, Oded Easton, Amy Sheng, Morgan Hansen, David V. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Meilandt, William J. Ngu, Hai Gogineni, Alvin Lalehzadeh, Guita Lee, Seung-Hye Srinivasan, Karpagam Imperio, Jose Wu, Tiffany Weber, Martin Kruse, Agatha J. Stark, Kimberly L. Chan, Pamela Kwong, Mandy Modrusan, Zora Friedman, Brad A. Elstrott, Justin Foreman, Oded Easton, Amy Sheng, Morgan Hansen, David V. |
| author_sort | Meilandt, William J. |
| collection | MIT |
| description | Copyright © 2020 Meilandt et al. TREM2 is an Alzheimer’s disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/ Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2 ko females at 6 –7 months; but by 12 or 19 –22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2 ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity. |
| first_indexed | 2024-09-23T10:54:08Z |
| format | Article |
| id | mit-1721.1/135187.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:54:08Z |
| publishDate | 2022 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/135187.22024-06-13T20:11:48Z Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model Meilandt, William J. Ngu, Hai Gogineni, Alvin Lalehzadeh, Guita Lee, Seung-Hye Srinivasan, Karpagam Imperio, Jose Wu, Tiffany Weber, Martin Kruse, Agatha J. Stark, Kimberly L. Chan, Pamela Kwong, Mandy Modrusan, Zora Friedman, Brad A. Elstrott, Justin Foreman, Oded Easton, Amy Sheng, Morgan Hansen, David V. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Copyright © 2020 Meilandt et al. TREM2 is an Alzheimer’s disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/ Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2 ko females at 6 –7 months; but by 12 or 19 –22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2 ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity. 2022-03-14T18:24:14Z 2021-10-27T20:22:21Z 2022-03-14T18:24:14Z 2020-01 2019-12 2021-03-18T17:32:13Z Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 https://hdl.handle.net/1721.1/135187.2 en http://dx.doi.org/10.1523/jneurosci.1871-19.2019 Journal of Neuroscience Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/octet-stream Society for Neuroscience Journal of Neuroscience |
| spellingShingle | Meilandt, William J. Ngu, Hai Gogineni, Alvin Lalehzadeh, Guita Lee, Seung-Hye Srinivasan, Karpagam Imperio, Jose Wu, Tiffany Weber, Martin Kruse, Agatha J. Stark, Kimberly L. Chan, Pamela Kwong, Mandy Modrusan, Zora Friedman, Brad A. Elstrott, Justin Foreman, Oded Easton, Amy Sheng, Morgan Hansen, David V. Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title | Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title_full | Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title_fullStr | Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title_full_unstemmed | Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title_short | Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model |
| title_sort | trem2 deletion reduces late stage amyloid plaque accumulation elevates the aβ42 aβ40 ratio and exacerbates axonal dystrophy and dendritic spine loss in the ps2app alzheimer s mouse model |
| url | https://hdl.handle.net/1721.1/135187.2 |
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