Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles
Alzheimer’s disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3703 |
| _version_ | 1797212486705872896 |
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| author | Christina Coughlan Jared Lindenberger Jeffrey G. Jacot Noah R. Johnson Paige Anton Shaun Bevers Robb Welty Michael W. Graner Huntington Potter |
| author_facet | Christina Coughlan Jared Lindenberger Jeffrey G. Jacot Noah R. Johnson Paige Anton Shaun Bevers Robb Welty Michael W. Graner Huntington Potter |
| author_sort | Christina Coughlan |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF. We propose that extracellular vesicles (EVs) play a role in this transport. EVs are found in bodily fluids such as blood, urine, and cerebrospinal fluid and carry diverse “cargos” of bioactive molecules (e.g., proteins, nucleic acids, lipids, metabolites) that dynamically reflect changes in the cells from which they are secreted. While Aβ42 and Aβ40 have been reported to be present in EVs, it is not known whether this interaction is specific for these peptides and thus whether amyloid-carrying EVs play a role in AD and/or serve as brain-specific biomarkers of the AD process. To determine if there is a specific interaction between Aβ and EVs, we used isothermal titration calorimetry (ITC) and discovered that Aβ42 and Aβ40 bind to EVs in a manner that is sequence specific, saturable, and endothermic. In addition, Aβ incubation with EVs overnight yielded larger amounts of bound Aβ peptide that was fibrillar in structure. These findings point to a specific amyloid–EV interaction, a potential role for EVs in the transport of amyloid from the brain to the blood, and a role for this amyloid pool in the AD process. |
| first_indexed | 2024-04-24T10:43:09Z |
| format | Article |
| id | doaj.art-377963c4b07f4f4d805feee00166b7e7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:43:09Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-377963c4b07f4f4d805feee00166b7e72024-04-12T13:19:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257370310.3390/ijms25073703Specific Binding of Alzheimer’s Aβ Peptides to Extracellular VesiclesChristina Coughlan0Jared Lindenberger1Jeffrey G. Jacot2Noah R. Johnson3Paige Anton4Shaun Bevers5Robb Welty6Michael W. Graner7Huntington Potter8University of Colorado Alzheimer’s and Cognition Center (CUACC), Linda Crnic Institute for Down Syndrome (LCI), Department of Neurology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAStructural Biology and Biophysics Core, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Bioengineering, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAUniversity of Colorado Alzheimer’s and Cognition Center (CUACC), Linda Crnic Institute for Down Syndrome (LCI), Department of Neurology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAUniversity of Colorado Alzheimer’s and Cognition Center (CUACC), Linda Crnic Institute for Down Syndrome (LCI), Department of Neurology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAStructural Biology and Biophysics Core, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAStructural Biology and Biophysics Core, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Neurosurgery, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAUniversity of Colorado Alzheimer’s and Cognition Center (CUACC), Linda Crnic Institute for Down Syndrome (LCI), Department of Neurology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl, Aurora, CO 80045, USAAlzheimer’s disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF. We propose that extracellular vesicles (EVs) play a role in this transport. EVs are found in bodily fluids such as blood, urine, and cerebrospinal fluid and carry diverse “cargos” of bioactive molecules (e.g., proteins, nucleic acids, lipids, metabolites) that dynamically reflect changes in the cells from which they are secreted. While Aβ42 and Aβ40 have been reported to be present in EVs, it is not known whether this interaction is specific for these peptides and thus whether amyloid-carrying EVs play a role in AD and/or serve as brain-specific biomarkers of the AD process. To determine if there is a specific interaction between Aβ and EVs, we used isothermal titration calorimetry (ITC) and discovered that Aβ42 and Aβ40 bind to EVs in a manner that is sequence specific, saturable, and endothermic. In addition, Aβ incubation with EVs overnight yielded larger amounts of bound Aβ peptide that was fibrillar in structure. These findings point to a specific amyloid–EV interaction, a potential role for EVs in the transport of amyloid from the brain to the blood, and a role for this amyloid pool in the AD process.https://www.mdpi.com/1422-0067/25/7/3703extracellular vesicles (EVs)amyloidisothermal titration calorimetry (ITC)atomic force microscopy (AFM) |
| spellingShingle | Christina Coughlan Jared Lindenberger Jeffrey G. Jacot Noah R. Johnson Paige Anton Shaun Bevers Robb Welty Michael W. Graner Huntington Potter Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles International Journal of Molecular Sciences extracellular vesicles (EVs) amyloid isothermal titration calorimetry (ITC) atomic force microscopy (AFM) |
| title | Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles |
| title_full | Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles |
| title_fullStr | Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles |
| title_full_unstemmed | Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles |
| title_short | Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles |
| title_sort | specific binding of alzheimer s aβ peptides to extracellular vesicles |
| topic | extracellular vesicles (EVs) amyloid isothermal titration calorimetry (ITC) atomic force microscopy (AFM) |
| url | https://www.mdpi.com/1422-0067/25/7/3703 |
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