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Ageing cells offer new target for Alzheimer's therapy
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THIS WEEK
Why Alzheimer’s hits older brains Discovery of brain cells that turn toxic as they age offers a tantalising target for treatment Jessica Hamzelou
ALZHEIMER’S disease is more prevalent in older people, but we have never known why. Now it seems that about 80 per cent of our brain cells are vulnerable to a process that can turn them toxic. For the first time, cells in the brains of people with Alzheimer’s have been shown to “senesce” – a mechanism that stops them 6 | NewScientist | 29 September 2012
in the body, such as those in the skin, lung and kidney, eventually accumulate DNA damage – typically with age. Not all of these damaged cells die though, instead some senesce. When this happens, biological changes within the cell prevent it from dividing or carrying out its normal functions. Research suggests that senescing cells also start producing proteins that trigger inflammation. “It’s pretty clear that cell senescence evolved to protect us against cancer,” says Judith Campisi of the Buck Institute for Research on Aging in Novato, California. The idea is that once
dividing and starts them on a path of destruction. With hundreds of experimental treatments for the disease falling by the wayside, we need a new target and it seems as if we have now found one. The discovery of huge numbers “This is important – if we of senescent cells in people with can clear senescent cells, Alzheimer’s suggests that they then we can probably play a key role in the condition. clear Alzheimer’s” Cells that continually replicate
cells accumulate DNA damage, they senesce to avoid incorrect division that can lead to cancer. The benefit of this mechanism over self-destruction is that it sends out a call to the immune system to destroy nearby cells that might also be affected. That mechanism may have worked well hundreds of years ago when we had shorter lifespans, but today it can trigger problems. The damaged cell isn’t killed, and goes on pumping out inflammatory proteins, which can cause the damage thought to underlie age-related ailments, such as failing organs. Claudio Torres at Drexel University College of Medicine in Philadelphia, Pennsylvania, wondered whether senescence might be the cause of the
In this section n Separating correlation and causality, page 8 n Birth pangs of a new tectonic plate boundary, page 10 n Robot snakes on a plane, page 18
A new direction The awful truth is sinking in: getting rid of the most obvious hallmarks of Alzheimer’s disease, the sticky plaques that clog up people’s brains, isn’t working. Last month, the two largest trials of treatments to attack plaques failed. In fact, between 1998 and 2011, 101 experimental treatments for Alzheimer’s were scrapped, with only three drugs making it to market. No one disputes that plaques, and the soluble beta-amyloid deposits from which they form, have an impact, but it’s becoming clear that earlier events may be key to treating the disease (see main story).
Several trials are now focusing on protecting synapses, the gaps across which neurons communicate. A cancer drug called bryostatin 1 has been shown to boost an enzyme, called PKC epsilon, that helps forms synapses, and protects them against plaques. Daniel Alkon of the Blanchette Rockefeller Neurosciences Institute in Morgantown, West Virginia, is about to begin a trial of the drug in people with Alzheimer’s. At University College London, Patricia Salinas and her colleagues have shown that soluble beta-amyloid raises concentrations of a synapsedestroying enzyme called Dkk1. When
people with the disease, with little and from people aged between success (see “A new direction”, 78 and 90. Healthy brains from above). So Torres also wanted to adults over 35 had six to eight know whether there was a times more senescent cells than the fetuses. Moreover, adults with connection between senescence and protein plaques. When his Alzheimer’s had more of these group put the plaque protein in cells than their Alzheimer’s-free dishes filled with astrocytes, they peers of a similar age. “The saw that the cells surrounding the amount of senescence is protein appeared to senesce. significant,” says Torres. In the Torres thinks the plaques and oldest brains, about 30 per cent ageing astrocytes get caught in a of the astrocytes seemed to have vicious circle – as the astrocytes senesced, and this figure was –The dance goes on– 10 per cent higher in those with senesce, they are less able to perform their plaque-clearing Alzheimer’s. inflammation in Alzheimer’s. duties, while the accumulation “For the first time, we’ve Neurons themselves don’t of plaques drives more cells to found senescent astrocytes in tend to replicate, but star-shaped the brain, which accumulate in “If you could keep the astrocytes do. These cells, thought Alzheimer’s,” he says. “It’s a new astrocytes young, to make up about 80 to 90 per way to look at the disease.” The they’d be able to clear cent of the brain, have a vital role finding may also explain why the plaques” in supporting neurons, including many other neurodegenerative clearing the beta-amyloid plaques diseases occur more frequently associated with Alzheimer’s. senesce (PLoS One, doi.org/jdz). with age. Torres and his colleagues What can we do to stop this “The inflammatory state is exposed human astrocytes to process? Torres’s team is now important for Alzheimer’s,” hydrogen peroxide – a compound says Felipe Sierra, director of the investigating whether delaying that triggers the kind of metabolic National Institute on Aging in the senescence of astrocytes stress that occurs with normal could stave off Alzheimer’s. Bethesda, Maryland. “We never ageing. Sure enough, the cells “If you could keep the astrocytes knew where the inflammatory stopped dividing and started young, they’d be able to clear the proteins came from – now this expressing genes associated with plaques,” he says. suggests they come from senescence. What’s more, the cells senescent astrocytes.” Preventing senescence might began releasing vast amounts of not be the best approach, though, For more than 20 years, inflammatory proteins. because it may increase the risk of researchers have been trying to Torres’s team then looked for cancer. Instead, it might be an idea treat Alzheimer’s by blocking the senescent cells in brain slices from accumulation of the waxy plaques to simply get rid of the senescent fetuses, from people aged 35 to 50 often found in the brains of cells. The technique has already
the enzyme was blocked in cultures of brain cells, synapses remained intact – potentially offering a way to protect the ageing brain. A third hope comes from a team led by Gary Landreth of Case Western Reserve University in Cleveland, Ohio. In mice, bexarotene, another cancer drug, got rid of half the plaques within three days. The drug also reduced levels of beta-amyloid and the animals rapidly recovered their cognitive abilities. Landreth cautions against assuming that the same would happen in humans, but is currently testing the drug in people without the condition.
been shown to have huge benefits in mice. Last year, James Kirkland and his colleagues at the Mayo Clinic in Rochester, Minnesota, found that removing all of the senescent cells in a mouse prevented the onset of a range of age-related disorders (Nature, doi. org/d9vd9c). This paper is particularly important, says Torres. “If we can clear senescent cells, then we can probably clear Alzheimer’s.” Sierra agrees. “Maybe we can remove senescent astrocytes and finally get some headway on Alzheimer’s,” he says. “This senescence is a very targetable thing.” The first step may be stopping senescing brain cells from secreting their inflammatory brew. Campisi and her colleagues have already achieved this in a dish of senescing cells from the body. “We’ve found a compound that suppresses the secretions of senescent cells,” she says. “Now we are working to scale it up.” “After 50 years of looking, we still have no cure for Alzheimer’s,” says Torres. “This finding opens up a new window that could be very important.” “It’s too early to know for sure, but it’s a tantalising possibility,” says Sierra. “It makes me very optimistic.” n 29 September 2012 | NewScientist | 7
THIS WEEK
Why Alzheimer’s hits older brains Discovery of brain cells that turn toxic as they age offers a tantalising target for treatment Jessica Hamzelou
ALZHEIMER’S disease is more prevalent in older people, but we have never known why. Now it seems that about 80 per cent of our brain cells are vulnerable to a process that can turn them toxic. For the first time, cells in the brains of people with Alzheimer’s have been shown to “senesce” – a mechanism that stops them 6 | NewScientist | 29 September 2012
in the body, such as those in the skin, lung and kidney, eventually accumulate DNA damage – typically with age. Not all of these damaged cells die though, instead some senesce. When this happens, biological changes within the cell prevent it from dividing or carrying out its normal functions. Research suggests that senescing cells also start producing proteins that trigger inflammation. “It’s pretty clear that cell senescence evolved to protect us against cancer,” says Judith Campisi of the Buck Institute for Research on Aging in Novato, California. The idea is that once
dividing and starts them on a path of destruction. With hundreds of experimental treatments for the disease falling by the wayside, we need a new target and it seems as if we have now found one. The discovery of huge numbers “This is important – if we of senescent cells in people with can clear senescent cells, Alzheimer’s suggests that they then we can probably play a key role in the condition. clear Alzheimer’s” Cells that continually replicate
cells accumulate DNA damage, they senesce to avoid incorrect division that can lead to cancer. The benefit of this mechanism over self-destruction is that it sends out a call to the immune system to destroy nearby cells that might also be affected. That mechanism may have worked well hundreds of years ago when we had shorter lifespans, but today it can trigger problems. The damaged cell isn’t killed, and goes on pumping out inflammatory proteins, which can cause the damage thought to underlie age-related ailments, such as failing organs. Claudio Torres at Drexel University College of Medicine in Philadelphia, Pennsylvania, wondered whether senescence might be the cause of the
In this section n Separating correlation and causality, page 8 n Birth pangs of a new tectonic plate boundary, page 10 n Robot snakes on a plane, page 18
A new direction The awful truth is sinking in: getting rid of the most obvious hallmarks of Alzheimer’s disease, the sticky plaques that clog up people’s brains, isn’t working. Last month, the two largest trials of treatments to attack plaques failed. In fact, between 1998 and 2011, 101 experimental treatments for Alzheimer’s were scrapped, with only three drugs making it to market. No one disputes that plaques, and the soluble beta-amyloid deposits from which they form, have an impact, but it’s becoming clear that earlier events may be key to treating the disease (see main story).
Several trials are now focusing on protecting synapses, the gaps across which neurons communicate. A cancer drug called bryostatin 1 has been shown to boost an enzyme, called PKC epsilon, that helps forms synapses, and protects them against plaques. Daniel Alkon of the Blanchette Rockefeller Neurosciences Institute in Morgantown, West Virginia, is about to begin a trial of the drug in people with Alzheimer’s. At University College London, Patricia Salinas and her colleagues have shown that soluble beta-amyloid raises concentrations of a synapsedestroying enzyme called Dkk1. When
people with the disease, with little and from people aged between success (see “A new direction”, 78 and 90. Healthy brains from above). So Torres also wanted to adults over 35 had six to eight know whether there was a times more senescent cells than the fetuses. Moreover, adults with connection between senescence and protein plaques. When his Alzheimer’s had more of these group put the plaque protein in cells than their Alzheimer’s-free dishes filled with astrocytes, they peers of a similar age. “The saw that the cells surrounding the amount of senescence is protein appeared to senesce. significant,” says Torres. In the Torres thinks the plaques and oldest brains, about 30 per cent ageing astrocytes get caught in a of the astrocytes seemed to have vicious circle – as the astrocytes senesced, and this figure was –The dance goes on– 10 per cent higher in those with senesce, they are less able to perform their plaque-clearing Alzheimer’s. inflammation in Alzheimer’s. duties, while the accumulation “For the first time, we’ve Neurons themselves don’t of plaques drives more cells to found senescent astrocytes in tend to replicate, but star-shaped the brain, which accumulate in “If you could keep the astrocytes do. These cells, thought Alzheimer’s,” he says. “It’s a new astrocytes young, to make up about 80 to 90 per way to look at the disease.” The they’d be able to clear cent of the brain, have a vital role finding may also explain why the plaques” in supporting neurons, including many other neurodegenerative clearing the beta-amyloid plaques diseases occur more frequently associated with Alzheimer’s. senesce (PLoS One, doi.org/jdz). with age. Torres and his colleagues What can we do to stop this “The inflammatory state is exposed human astrocytes to process? Torres’s team is now important for Alzheimer’s,” hydrogen peroxide – a compound says Felipe Sierra, director of the investigating whether delaying that triggers the kind of metabolic National Institute on Aging in the senescence of astrocytes stress that occurs with normal could stave off Alzheimer’s. Bethesda, Maryland. “We never ageing. Sure enough, the cells “If you could keep the astrocytes knew where the inflammatory stopped dividing and started young, they’d be able to clear the proteins came from – now this expressing genes associated with plaques,” he says. suggests they come from senescence. What’s more, the cells senescent astrocytes.” Preventing senescence might began releasing vast amounts of not be the best approach, though, For more than 20 years, inflammatory proteins. because it may increase the risk of researchers have been trying to Torres’s team then looked for cancer. Instead, it might be an idea treat Alzheimer’s by blocking the senescent cells in brain slices from accumulation of the waxy plaques to simply get rid of the senescent fetuses, from people aged 35 to 50 often found in the brains of cells. The technique has already
the enzyme was blocked in cultures of brain cells, synapses remained intact – potentially offering a way to protect the ageing brain. A third hope comes from a team led by Gary Landreth of Case Western Reserve University in Cleveland, Ohio. In mice, bexarotene, another cancer drug, got rid of half the plaques within three days. The drug also reduced levels of beta-amyloid and the animals rapidly recovered their cognitive abilities. Landreth cautions against assuming that the same would happen in humans, but is currently testing the drug in people without the condition.
been shown to have huge benefits in mice. Last year, James Kirkland and his colleagues at the Mayo Clinic in Rochester, Minnesota, found that removing all of the senescent cells in a mouse prevented the onset of a range of age-related disorders (Nature, doi. org/d9vd9c). This paper is particularly important, says Torres. “If we can clear senescent cells, then we can probably clear Alzheimer’s.” Sierra agrees. “Maybe we can remove senescent astrocytes and finally get some headway on Alzheimer’s,” he says. “This senescence is a very targetable thing.” The first step may be stopping senescing brain cells from secreting their inflammatory brew. Campisi and her colleagues have already achieved this in a dish of senescing cells from the body. “We’ve found a compound that suppresses the secretions of senescent cells,” she says. “Now we are working to scale it up.” “After 50 years of looking, we still have no cure for Alzheimer’s,” says Torres. “This finding opens up a new window that could be very important.” “It’s too early to know for sure, but it’s a tantalising possibility,” says Sierra. “It makes me very optimistic.” n 29 September 2012 | NewScientist | 7