For most patients, Alzheimer's disease starts with trivial things like forgetting where the car keys are. At a later stage, it robs us of something at the core of our humanity—our memories and identity.
The consensus today is that Alzheimer’s disease develops from multiple factors such as genetics, lifestyle and the environment. And yet, considerable debate persists on the role of peptide aggregates of amyloid-β (Aβ)—that form plaques in the brains of Alzheimer’s patients. It is unclear if the peptides themselves are neurotoxic, or only involved in the initiation of the diseases, or if they are simply a byproduct of the disease.
To examine the role of soluble Aβ oligomers in disease initiation, a team of scientists based in Singapore turned to a powerful, new technique called optogenetics, which uses a combination of light and genetic engineering to selectively control neuronal cells in the brain.
“Optogenetics allows for excellent control, both spatially and temporally, as light is used to trigger events,” said study co-author Ajay Mathuru a Joint Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Yale-NUS College. “Inducing Aβ peptide oligomerization with blue light in vivo allows us to study early events that may be happening naturally when the peptides oligomerize.”
Working with three model organisms (zebrafish, worms and flies), the researchers expressed fluorescently tagged Aβ peptides in specific neurons and induced them to oligomerize rapidly in the presence of blue light. Aβ expression reduced the lifespan and reproductive fitness of the animals tested, and Aβ aggregation caused further metabolic effects and tissue loss that resembled patients with late-stage Alzheimer’s.
As a proof-of-concept that their optogenetic system can be used to identify potential new treatments for Alzheimer’s, the researchers showed that lithium treatment—a known neuroprotective agent—increased the lifespan of fruit flies with Aβ aggregates and reduced the number of Aβ clusters in cultured cells.
This optogenetics study allowed the research team to test a hypothesis across three model organisms. While Mathuru’s lab works on zebrafish (Danio rerio), expertise in worms (Caenorhabditis elegans) and flies (Drosophila melanogaster) was provided by Yale-NUS colleagues Jan Gruber and Nicholas Tolwinski, respectively.
“Each model organism has different advantages as a system. This kind of multi-model approach is powerful as we could play to the strengths of each of these systems and combine complementary strategies to perform metabolic and biochemical studies, aging studies, genetic analysis, and neurobiological studies,” Mathuru said.
Because optogenetic Aβ expression can be restricted to specific neurons, the researchers plan on finding out if specific neuronal types, such as serotonergic or dopaminergic neurons, are more susceptible to the neurotoxic effects of oligomerization.
The A*STAR-affiliated researchers contributing to this research are from A*STAR’s Institute of Molecular and Cell Biology (IMCB).