Application of optogenetic Amyloid- β distinguishes between metabolic and physical damage 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 an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiolog y of Alzheimer's Disease is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separatein 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 Alzheimer's Disease. We us eDrosophila,C. elegans andD. 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 ...
Source: eLife - Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research