Abstract
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.
Highlights
Alzheimer’s disease (AD) is a debilitating, age-associated, neurodegenerative disease which affects more than 46.8 million people worldwide and represents the 6th leading cause of death in the United States of America (Ahn et al, 2001; De-Paula et al, 2012; Hawkes, 2016; Kumar et al, 2015; Zhang et al, 2011)
The AD clinical trial landscape has largely been dominated by the amyloid cascade hypothesis, with more than 50% of the drugs targeting amyloid beta (Ab) in Phase III trials alone (Cummings et al, 2018)
To address the role of aggregation of intracellular Ab in the pathophysiological effects of AD, we developed a light-inducible system for use in model organisms
Summary
Alzheimer’s disease (AD) is a debilitating, age-associated, neurodegenerative disease which affects more than 46.8 million people worldwide and represents the 6th leading cause of death in the United States of America (Ahn et al, 2001; De-Paula et al, 2012; Hawkes, 2016; Kumar et al, 2015; Zhang et al, 2011). Despite extensive efforts over the last 50 years, no disease-modifying therapy has been found and, most recently, several high-profile Phase III clinical trials have failed (Anderson et al, 2017; Lim and Mathuru, 2018; Park et al, 2018). The AD clinical trial landscape has largely been dominated by the amyloid cascade hypothesis, with more than 50% of the drugs targeting amyloid beta (Ab) in Phase III trials alone (Cummings et al, 2018). The causative role of Ab plaques has recently been challenged, because of the failure of numerous interventions targeting Ab plaques in Phase III trials and the observation of Ab plaques in brains of non-AD symptomatic individuals (Cummings, 2018).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
