Scientists have discovered a natural mechanism the body uses to protect against cancer could be the reason brain cells in people with Alzheimer’s disease deteriorate so rapidly. They hope their discovery will (for the first time) offer a target for treating the disease.
“Aging is the main risk factor for Alzheimer’s disease,” they write in an article about their work which appeared online in the 12 September issue of the open access journal PLoS ONE.
However, we know little about which aspects of the aging process make the brain susceptible to the development of Alzheimer’s, they add.
In their paper, Claudio Torres of Drexel University College of Medicine in Philadelphia, and colleagues, show for the first time, how brain cells of people with Alzheimer’s “senesce”: a mechanism where as a result of accumulated DNA damage, cells stop dividing and doing their usual work, and start producing toxic proteins instead.
The older we are, the more times the cells in our bodies have replicated. However, with each replication cycle, there is some DNA damage, so each generation of cells accumulates more DNA damage, until it is so great, there is a high chance they will go out of control and start forming a tumor. The body has evolved mechanisms to protect itself against that.
One such mechanism the body has acquired for protecting against the risks of accumulated DNA damage is to trigger “apoptosis” or cell suicide, allowing affected cells to die off and be mopped up by the immune system. This is often seen in cells that replicate continually, such as those of skin, lung and kidney.
But not all DNA-damaged cells go down the cell suicide route: some of them go down another path known as “senescence”, where biological changes stop the cells dividing and carrying out their normal fuctions, and switch them into making toxic proteins instead.
There is some evidence that this process also triggers inflammation.
Senescence has a different effect on the immune system to apoptosis: it causes it to carry out a damage-limitation exercise and destroy nearby cells that might be affected by the toxins.
Judith Campisi of the Buck Institute for Research on Aging in Novato, California, who was not involved in the study, told New Scientist magazine that it was “pretty clear” that senescence evolved as an anti-cancer mechanism.
However, what evolution has produced may have been helpful when human life expectancy was shorter, but it becomes counter-productive once that age threshold is past, because by not dying off, those senescent cells can continue to produce toxins that produce inflammation.
It was wondering about this problem that caused Torres and colleagues to propose that perhaps senescent cells are what causes inflammation in Alzheimer’s disease.
So for their study, they simulated the effects of aging by exposing brain cells to hydrogen peroxide (this produces a metabolic stress similar to that caused by aging) and observed what happened. They found the cells stopped dividing, started expressing genes associated with senescence, and secreting large quantities of inflammatory protein.
The cells that were doing this weren’t neurons, the cells that carry out the mental functions of the brain (they tend not to replicate), but astrocytes, a group of star-shaped cells that make up about 80 to 90% of the brain. Astrocytes support neurons by doing vital work like clearing away the beta-amyloid plaques that are characteristic of Alzheimer’s.
Torres and colleagues carried out their experiment in brain samples from fetuses, from people aged 35 to 50, and from people aged 78 to 90.
They found healthy brains from people over 35 had up to 8 times more senescent cells than fetuses.
And they also found that in healthy brains of 80 and 90 year-olds, up to 30% of astrocytes had gone down the senescence route. But in people with Alzheimer’s, this figure was about 10% higher.
They propose that an accumulation of senescent astrocytes “may link increased age and increased risk for sporadic Alzheimer’s disease”.
According to New Scientist, Torres says their study provides a new way to look at Alzheimer’s, and it might also shed light on other neurodegenerative diseases for which age is a risk factor.
But he does not advise preventing senescence altogether as a way forward: it is a natural mechanism against cancer. Instead, perhaps targeting damaged cells is an option:
“If we can clear senescent cells, then we can probably clear Alzheimer’s,” he suggests.
Written by Catharine Paddock PhD