Alzheimer's, yeasts and other animals
“A major breakthrough in Alzheimer’s research holds out hope not only of early detection of the crippling brain disease but also potential new treatments,” reports the Daily Express.
The headline is based on research into a peptide (small protein) called amyloid beta that is linked to Alzheimer’s disease. This protein is found in plaques (deposits) in the brains of Alzheimer’s patients and, according to one theory, is responsible for the disease. The researchers created a type of genetically modified yeast and used it to identify genes that could alter the toxic effect of amyloid beta. They found that the genes they identified also changed the toxic effect of amyloid beta in worms and rat brain cells. A further experiment in the yeast showed that amyloid beta disrupted a process called endocytosis in yeast cells. In endocytosis, cells take up and transport substances around the cell. This process also occurs in human cells, and genes involved in this process have already been identified as risk factors for Alzheimer’s disease.
This sort of research is important in working towards treatments for Alzheimer’s disease. However, this is early research and although the researchers are confident that these findings apply to humans, we will still need to wait for research using human cells before this can be confirmed. New treatments and diagnostic tools based on these findings are a long way off.
Where did the story come from?
The study was carried out by researchers from the Whitehead Institute for Biomedical Research, and a number of other American and international universities and research centres. It was funded by an HHMI collaborative Innovation Award, an NRSA fellowship, the Cure Alzheimer’s Fund, the US National Institutes of Health (NIH), the Kempe Foundation and Alzheimerfonden.
The study was published in the peer-reviewed journal Science.
Contrary to the report in the Daily Express, new diagnostic tests for Alzheimer’s and new treatments based on this research are not on the horizon. Instead, this early research investigated the reason for the toxicity of the amyloid beta protein, and whether other genes can influence it. Any practical application is probably years away.
What kind of research was this?
This was a laboratory study that involved experiments in yeast, worms and cultured rat brain cells to try to identify other genes that are involved in amyloid beta toxicity. Amyloid beta is the peptide (small protein) implicated in Alzheimer’s disease as it is found in plaques (deposits) in the brains of Alzheimer’s patients. The researchers aimed to understand further what happens during Alzheimer’s disease, and why the amyloid beta peptide is toxic.
A laboratory-based study is the only way that this type of question can be answered. In this study, the findings in yeast were validated in worms and mammalian cells. Many of the genes identified are present in humans, and mutations in the genes encoding these proteins have been linked to susceptibility to Alzheimer’s disease. The process that amyloid beta was shown to affect (endocytosis) is common to human cells. However, further research will have to be performed to confirm whether the findings hold true in humans.
What did the research involve?
The researchers decided first to test amyloid beta toxicity in modified yeast cells. To do this, they introduced into the yeast cells DNA that encoded amyloid beta. They then forced the cells to overexpress amyloid beta. They added a special targeting sequence to the end of amyloid beta so that it would move through the yeast cell in a similar way to that in which it moves through human cells. The researchers also constructed other control strains that overexpressed other proteins with similar properties. They then looked at the amyloid beta peptide that was produced, to confirm whether it behaved in a similar manner to amyloid beta in mammals.
A genetic screen was then performed using this yeast model. In this screen, strains which overexpressed every gene which codes for a protein were created. The researchers tried to identify two gene types. One, when overexpressed, could reverse the reduction in growth of yeast caused by expression of amyloid beta, so growth was increased (termed suppressors). The second could add to it, so growth of the yeast was further reduced (termed enhancers). The researchers then investigated whether equivalent genes are also present in human DNA, and whether they have been implicated in Alzheimer’s disease susceptibility.
The researchers then determined whether the modifiers of amyloid beta toxicity they identified had an effect on the viability of neurons (brain cells). To do this experiment, they used a type of worm called C. elegans, which they genetically modified so it expressed the amyloid beta peptide only in glutamatergic neurons, a particular type of neuron that is especially vulnerable in Alzheimer’s disease. The researchers chose C. elegans because it has been extensively studied, and the location and number of glutamatergic neurons is known.
The effect of one of the suppressors, PICALM, on the toxicity of amyloid beta aggregates was investigated in more detail in cultured rat neurons.
The researchers then returned to the yeast cells to investigate how PICALM may reduce the toxicity of amyloid beta.
What were the basic results?
The researchers found that overexpression of amyloid beta decreased cell growth. The overexpression of other similar proteins was less toxic, demonstrating that the amyloid beta peptide itself was responsible for the toxicity. The amyloid beta peptide that was produced was of the correct size and was localised correctly in the cell. It could also aggregate, or stick together. These amyloid beta aggregates form the amyloid plaques seen in Alzheimer’s disease.
Twenty-three suppressors, which reversed the reduced growth seen when amyloid beta was overexpressed, and 17 enhancers, which reduced growth further, were identified. Twelve of the modifiers of the effect of amyloid beta had clear human equivalents (homologues), and the researchers concentrated on these. Many of the modifiers are associated with Alzheimer’s disease susceptibility, for example the human homologue of yeast YAP1802 is PICALM, which research indicates is a risk factor for sporadic Alzheimer’s disease.
Expression of amyloid beta caused the age-dependent loss of glutamatergic neurons in C. elegans. The researchers tested the effect of overexpressing the modifiers they identified in yeast. Overexpression of C. elegans homologues of every gene they tested had a similar effect: either decreasing or increasing the loss of neurons. PICALM was found to suppress the toxicity of amyloid beta aggregates on cultured rat neurons.
Using the yeast system they created, they found that amyloid beta affects a process termed endocytosis. Endocytosis is a process by which the cell brings substances into the cell. Amyloid beta also affects how these substances are then moved around once in the cell (termed trafficking). Yeast YAP1802 and its human homologue PICALM has already been shown to be involved in endocytosis and trafficking, and overexpression of YAP1802 compensates for the effects amyloid beta has on these processes.
How did the researchers interpret the results?
The researchers conclude that throughout the diverse organisms examined in this study, “endocytosis is a critical point of vulnerability to [amyloid beta]”. They also say that the yeast model that they have created “provides a tool for identifying genetic leads, investigating their mechanisms of action, and screening for genetic and small molecule modifiers” of Alzheimer’s disease.
In this study, the researchers used yeast, worms and cultured rat brain cells to model the effect of amyloid beta, the peptide (small protein) implicated in Alzheimer’s disease. The researchers aimed to understand further what happens during Alzheimer’s disease, and why the amyloid beta peptide is toxic.
They created a yeast model of amyloid beta toxicity. Using this model, they identified genes that altered the effect of the amyloid beta peptide. Many of these genes had clear human equivalents, which have already been linked to Alzheimer’s disease susceptibility. The researchers then confirmed their findings by investigating the effect of amyloid beta and the modifier genes on worm neurons. They further investigated PICALM, a highly probable human Alzheimer’s disease risk factor, which had been identified during the study. They found that overexpression increased survival of rat neurons treated with amyloid beta aggregates.
Returning to the yeast model, the researchers investigated why the amyloid beta peptide was toxic, and how some of the modifiers could be changing the toxicity of amyloid beta. As several genes are involved in the update of substances from outside the cell and the movement of these substances inside the cell (processes called endocytosis and trafficking), they examined whether amyloid beta was affecting these processes, and found that it was.
This research has demonstrated that a variety of model systems can be used to explore the causes of Alzheimer’s disease. It has also provided reasons why certain genes might be genetic risk factors. Further research could help understand the process behind Alzheimer’s disease.
This sort of research is important and vital to working towards treatments for Alzheimer’s disease. However, this is early research and although the researchers are confident that these findings apply to humans, we will still need to wait for research using human cells. New treatments and diagnostic tools based on these findings are a long way off.
- Treusch S, Hamamichi S, Goodman JL, et al. Functional Links Between Aβ Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast. Science 2011, Published online October 27.
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