A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner
Abstract ApoE-ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), linked to increased amyloid-β (Aβ) deposition in the brain. In AD mouse models, microglial expression of apoE3 reduces amyloid plaque burden through enhanced phagocytosis, whereas apoE4 is associated with...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01524-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850203970618785792 |
|---|---|
| author | Sourav Dasadhikari Shamasree Ghosh Sudip Pal Tuomas P. J. Knowles Kanchan Garai |
| author_facet | Sourav Dasadhikari Shamasree Ghosh Sudip Pal Tuomas P. J. Knowles Kanchan Garai |
| author_sort | Sourav Dasadhikari |
| collection | DOAJ |
| description | Abstract ApoE-ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), linked to increased amyloid-β (Aβ) deposition in the brain. In AD mouse models, microglial expression of apoE3 reduces amyloid plaque burden through enhanced phagocytosis, whereas apoE4 is associated with impaired Aβ clearance. However, the isoform-specific interactions of apoE with Aβ aggregates and the molecular mechanisms by which these isoforms influence Aβ aggregation and clearance remain poorly understood, which is critical for developing potential therapeutic interventions. Here, we employed TIRFM, superresolution microscopy, and single-molecule photobleaching techniques to investigate the isoform-specific effects of apoE on the rate constants of Aβ42 aggregation at the single-fibril level, as well as to quantify the binding affinity and specificity of apoE isoforms to individual Aβ fibril ends. Our results show that apoE4 is ca. 4–5 times less effective than apoE3 and apoE2 in inhibiting fibril elongation, while secondary nucleation is largely unaffected by any of the isoforms. Furthermore, apoE3 exhibits stronger and more specific binding to fibril ends compared to apoE4. These findings suggest that apoE4’s reduced affinity for growing fibril ends may impair microglial clearance and increase amyloid deposition through a higher elongation rate in the brain of ApoE-ε4 carriers. |
| format | Article |
| id | doaj-art-60dd6db78b2c4221bf5561fcd2de0cc3 |
| institution | OA Journals |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-60dd6db78b2c4221bf5561fcd2de0cc32025-08-20T02:11:22ZengNature PortfolioCommunications Chemistry2399-36692025-04-018111210.1038/s42004-025-01524-zA single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent mannerSourav Dasadhikari0Shamasree Ghosh1Sudip Pal2Tuomas P. J. Knowles3Kanchan Garai4TIFR Centre for Interdisciplinary SciencesTIFR Centre for Interdisciplinary SciencesTIFR Centre for Interdisciplinary SciencesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of CambridgeTIFR Centre for Interdisciplinary SciencesAbstract ApoE-ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), linked to increased amyloid-β (Aβ) deposition in the brain. In AD mouse models, microglial expression of apoE3 reduces amyloid plaque burden through enhanced phagocytosis, whereas apoE4 is associated with impaired Aβ clearance. However, the isoform-specific interactions of apoE with Aβ aggregates and the molecular mechanisms by which these isoforms influence Aβ aggregation and clearance remain poorly understood, which is critical for developing potential therapeutic interventions. Here, we employed TIRFM, superresolution microscopy, and single-molecule photobleaching techniques to investigate the isoform-specific effects of apoE on the rate constants of Aβ42 aggregation at the single-fibril level, as well as to quantify the binding affinity and specificity of apoE isoforms to individual Aβ fibril ends. Our results show that apoE4 is ca. 4–5 times less effective than apoE3 and apoE2 in inhibiting fibril elongation, while secondary nucleation is largely unaffected by any of the isoforms. Furthermore, apoE3 exhibits stronger and more specific binding to fibril ends compared to apoE4. These findings suggest that apoE4’s reduced affinity for growing fibril ends may impair microglial clearance and increase amyloid deposition through a higher elongation rate in the brain of ApoE-ε4 carriers.https://doi.org/10.1038/s42004-025-01524-z |
| spellingShingle | Sourav Dasadhikari Shamasree Ghosh Sudip Pal Tuomas P. J. Knowles Kanchan Garai A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner Communications Chemistry |
| title | A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner |
| title_full | A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner |
| title_fullStr | A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner |
| title_full_unstemmed | A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner |
| title_short | A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner |
| title_sort | single fibril study reveals that apoe inhibits the elongation of aβ42 fibrils in an isoform dependent manner |
| url | https://doi.org/10.1038/s42004-025-01524-z |
| work_keys_str_mv | AT souravdasadhikari asinglefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT shamasreeghosh asinglefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT sudippal asinglefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT tuomaspjknowles asinglefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT kanchangarai asinglefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT souravdasadhikari singlefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT shamasreeghosh singlefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT sudippal singlefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT tuomaspjknowles singlefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner AT kanchangarai singlefibrilstudyrevealsthatapoeinhibitstheelongationofab42fibrilsinanisoformdependentmanner |