ZFIN ID: ZDB-PUB-200422-4
Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration
Lim, C.H., Kaur, P., Teo, E., Lam, V.Y.M., Zhu, F., Kibat, C., Gruber, J., Mathuru, A.S., Tolwinski, N.S.
Date: 2020
Source: eLIFE   9: (Journal)
Registered Authors: Kibat, Caroline, Mathuru, Ajay
Keywords: Alzheimer's disease, C. elegans, D. melanogaster, developmental biology, neuroscience, optogenetics, zebrafish
MeSH Terms:
  • Alzheimer Disease/drug therapy
  • Alzheimer Disease/physiopathology
  • Amyloid beta-Peptides/genetics*
  • Amyloid beta-Peptides/metabolism*
  • Animals
  • Brain/physiopathology*
  • Brain/radiation effects
  • Caenorhabditis elegans
  • Disease Progression
  • Drosophila
  • Female
  • HEK293 Cells
  • Humans
  • Light*
  • Lithium/administration & dosage
  • Male
  • Neurodegenerative Diseases
  • Optogenetics/methods*
  • Plaque, Amyloid
  • Zebrafish
PubMed: 32228858 Full text @ Elife
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.