杏吧原创

ALZHEIMER鈥橲 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鈥檚 have been shown to 鈥渟enesce鈥� 鈥� 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.

The discovery of huge numbers of senescent cells in people with Alzheimer鈥檚 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 鈥� 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.

鈥淚t鈥檚 pretty clear that cell senescence evolved to protect us against cancer,鈥� 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鈥檛 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鈥檚.

Neurons themselves don鈥檛 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鈥檚.

Torres and his colleagues exposed human astrocytes to hydrogen peroxide 鈥� 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鈥檚 more, the cells began releasing vast amounts of inflammatory proteins.

Torres鈥檚 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. Healthy brains from adults over 35 had six to eight times more senescent cells than the fetuses. Moreover, adults with Alzheimer鈥檚 had more of these cells than their Alzheimer鈥檚-free peers of a similar age. 鈥淭he amount of senescence is significant,鈥� 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鈥檚.

鈥淔or the first time, we鈥檝e found senescent astrocytes in the brain, which accumulate in Alzheimer鈥檚,鈥� he says. 鈥淚t鈥檚 a new way to look at the disease.鈥� The finding may also explain why many other neurodegenerative diseases occur more frequently with age.

鈥淭he inflammatory state is important for Alzheimer鈥檚,鈥� says , director of the National Institute on Aging in Bethesda, Maryland. 鈥淲e never knew where the inflammatory proteins came from 鈥� now this suggests they come from senescent astrocytes.鈥�

For more than 20 years, researchers have been trying to treat Alzheimer鈥檚 by blocking the accumulation of the waxy plaques often found in the brains of people with the disease, with little success (see 鈥�A new direction鈥�). 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 鈥� 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鈥檚 team is now investigating whether delaying the senescence of astrocytes could stave off Alzheimer鈥檚. 鈥淚f you could keep the astrocytes young, they鈥檇 be able to clear the plaques,鈥� he says.

鈥淚f you could keep the astrocytes young, they鈥檇 be able to clear the plaques鈥�

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. 鈥淚f we can clear senescent cells, then we can probably clear Alzheimer鈥檚.鈥�

鈥淭his is important 鈥� if we can clear senescent cells, then we can probably clear Alzheimer鈥檚鈥�

Sierra agrees. 鈥淢aybe we can remove senescent astrocytes and finally get some headway on Alzheimer鈥檚,鈥� he says. 鈥淭his senescence is a very targetable thing.鈥�

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. 鈥淲e鈥檝e found a compound that suppresses the secretions of senescent cells,鈥� she says. 鈥淣ow we are working to scale it up.鈥�

鈥淎fter 50 years of looking, we still have no cure for Alzheimer鈥檚,鈥� says Torres. 鈥淭his finding opens up a new window that could be very important.鈥�

鈥淚t鈥檚 too early to know for sure, but it鈥檚 a tantalising possibility,鈥� says Sierra. 鈥淚t makes me very optimistic.鈥�