Summary: Animal study reveals the formation of amyloid plaques drives brain tissue loss and neurodegeneration in Alzheimer’s disease. However, lithium, a drug commonly used to treat bipolar disorder, reduces the life-shortening effects of the loss.
Amyloid plaque formation directly causes brain tissue loss in animals, but a drug called lithium reduces the life-shortening effects of this loss, shows a study published today in eLife.
Patients with Alzheimer’s disease experience progressive memory loss and loss of brain matter over time. This study provides new details about what happens in the brain in Alzheimer’s disease and suggests a potential strategy to slow it.
Both the production of small protein fragments called Amyloid-ß and the assembly of these fragments into large clusters or plaques have been implicated in Alzheimer’s disease. But teasing apart the role of Amyloid-ß versus the role of plaque formation has been difficult.
“There is currently a lack of tools that can directly control the formation of Amyloid-ß plaques in animals, which would allow scientists to examine the effects of plaque formation in Alzheimer’s disease,” explains lead author Lim Chu Hsien, a researcher at, and recent graduate of Yale-NUS College, Singapore, who is currently pursuing her medical degree at Duke-NUS Medical School, Singapore.
Using a technique called optogenetics, Lim and her colleagues were able to engineer Amyloid-ß fragments that would form plaques when exposed to light in the brains of fruit flies, tiny worms and zebrafish. The experiments showed that both the presence of Amyloid-ß and the formation of plaques were detrimental to the lifespan and health of these animals.
The team found that formation of the plaques caused both metabolic problems in the brain and physical damage that led to a loss of brain tissue. It also impaired the animals’ sensory motor skills and behaviour.
Next, the researchers tested whether a drug called lithium that is used to treat some psychiatric disorders might mitigate the harm caused by light-induced plaque formation in fruit flies. They added lithium to the flies’ food and found that this led to an extended lifespan in the insects.
“These data demonstrate the potential use of our optogenetics system for Alzheimer’s disease drug testing,” explains senior author Nicholas Tolwinski, Associate Professor of Science (Life Sciences) at Yale-NUS College, Singapore. “This light-driven plaque formation approach could be used in cells to enable mass screening of potential treatments. It might also help scientists study the effects of treatments on the different stages of Alzheimer’s disease development.”
About this neuroscience research article
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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 aetiology of Alzheimer’s Disease 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 Alzheimer’s Disease. 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.