Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration
The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/52589 |
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| author | Chu Hsien Lim Prameet Kaur Emelyne Teo Vanessa Yuk Man Lam Fangchen Zhu Caroline Kibat Jan Gruber Ajay S Mathuru Nicholas S Tolwinski |
| author_facet | Chu Hsien Lim Prameet Kaur Emelyne Teo Vanessa Yuk Man Lam Fangchen Zhu Caroline Kibat Jan Gruber Ajay S Mathuru Nicholas S Tolwinski |
| author_sort | Chu Hsien Lim |
| collection | DOAJ |
| description | The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression. |
| first_indexed | 2024-04-14T07:50:27Z |
| format | Article |
| id | doaj.art-92b095df61944eb6979288e58c478d4a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:50:27Z |
| publishDate | 2020-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-92b095df61944eb6979288e58c478d4a2022-12-22T02:05:13ZengeLife Sciences Publications LtdeLife2050-084X2020-03-01910.7554/eLife.52589Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegenerationChu Hsien Lim0https://orcid.org/0000-0001-6691-8277Prameet Kaur1Emelyne Teo2https://orcid.org/0000-0001-5050-4109Vanessa Yuk Man Lam3Fangchen Zhu4Caroline Kibat5Jan Gruber6https://orcid.org/0000-0003-3329-3789Ajay S Mathuru7https://orcid.org/0000-0003-4591-5274Nicholas S Tolwinski8https://orcid.org/0000-0002-8507-2737Science Division, Yale- NUS College, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore; Department of Physiology, YLL School of Medicine, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, Singapore; Department of Biochemistry, National University of Singapore, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore; Department of Physiology, YLL School of Medicine, Singapore, SingaporeScience Division, Yale- NUS College, Singapore, SingaporeThe brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.https://elifesciences.org/articles/52589optogeneticsAlzheimer's disease |
| spellingShingle | Chu Hsien Lim Prameet Kaur Emelyne Teo Vanessa Yuk Man Lam Fangchen Zhu Caroline Kibat Jan Gruber Ajay S Mathuru Nicholas S Tolwinski Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration eLife optogenetics Alzheimer's disease |
| title | Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration |
| title_full | Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration |
| title_fullStr | Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration |
| title_full_unstemmed | Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration |
| title_short | Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration |
| title_sort | application of optogenetic amyloid β distinguishes between metabolic and physical damages in neurodegeneration |
| topic | optogenetics Alzheimer's disease |
| url | https://elifesciences.org/articles/52589 |
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