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 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.
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The discovery of huge numbers of senescent cells in people with Alzheimer’s suggests that they play a key role in the condition. Cells that continually replicate 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 of the Buck Institute for Research on Aging in Novato, California. The idea is that once 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.
at Drexel University College of Medicine in Philadelphia, Pennsylvania, wondered whether senescence might be the cause of the inflammation in Alzheimer’s.
Neurons themselves don’t tend to replicate, but star-shaped astrocytes do. These cells, thought to make up about 80 to 90 per cent of the brain, have a vital role in supporting neurons, including clearing the beta-amyloid plaques associated with Alzheimer’s.
Torres and his colleagues exposed human astrocytes to hydrogen peroxide – a compound that triggers the kind of metabolic stress that occurs with normal ageing. Sure enough, the cells stopped dividing and started expressing genes associated with senescence. What’s more, the cells began releasing vast amounts of inflammatory proteins.
Torres’s team then looked for senescent cells in brain slices from fetuses, from people aged 35 to 50 and from people aged between 78 and 90. ÎçŇą¸ŁŔű1000ĽŻşĎy brains from adults over 35 had six to eight times more senescent cells than the fetuses. Moreover, adults with Alzheimer’s had more of these cells than their Alzheimer’s-free peers of a similar age. “The amount of senescence is significant,” says Torres. In the oldest brains, about 30 per cent of the astrocytes seemed to have senesced, and this figure was 10 per cent higher in those with Alzheimer’s.
“For the first time, we’ve found senescent astrocytes in the brain, which accumulate in Alzheimer’s,” he says. “It’s a new way to look at the disease.” The finding may also explain why many other neurodegenerative diseases occur more frequently with age.
“The inflammatory state is important for Alzheimer’s,” says , director of the National Institute on Aging in Bethesda, Maryland. “We never knew where the inflammatory proteins came from – now this suggests they come from senescent astrocytes.”
For more than 20 years, researchers have been trying to treat Alzheimer’s by blocking the accumulation of the waxy plaques often found in the brains of people with the disease, with little success (see “A new direction“). So Torres also wanted to know whether there was a connection between senescence and protein plaques. When his group put the plaque protein in dishes filled with astrocytes, they saw that the cells surrounding the protein appeared to senesce.
Torres thinks the plaques and ageing astrocytes get caught in a vicious circle – as the astrocytes senesce, they are less able to perform their plaque-clearing duties, while the accumulation of plaques drives more cells to senesce ().
What can we do to stop this process? Torres’s team is now investigating whether delaying the senescence of astrocytes could stave off Alzheimer’s. “If you could keep the astrocytes young, they’d be able to clear the plaques,” he says.
“If you could keep the astrocytes young, they’d be able to clear the plaques”
Preventing senescence might not be the best approach, though, because it may increase the risk of cancer. Instead, it might be an idea to simply get rid of the senescent cells. The technique has already been shown to have huge benefits in mice. Last year, 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 ().
This paper is particularly important, says Torres. “If we can clear senescent cells, then we can probably clear Alzheimer’s.”
“This is important – 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.”
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. 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, and her colleagues have shown that soluble beta-amyloid raises concentrations of a synapse-destroying enzyme called Dkk1. When 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 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. Andy Coghlan
