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-beta plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-beta 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-beta peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-beta oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-beta peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-beta 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-beta were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-beta oligomerization from Amyloid-beta expression alone. The physical damage caused by Amyloid-beta oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-beta oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.