A STRANGE property marks out the brain cells of people with Alzheimer鈥檚: they have a glut of cells with more than the standard two sets of chromosomes. Furthermore, these turn out to be the cells most likely to perish in the late stages of the disease. The twin discoveries could drive research into one of the modern world鈥檚 most devastating neurological conditions in an entirely new direction.
No one can agree on the cause of Alzheimer鈥檚 disease. While much of the focus has been on the plaques that clog up the brains of sufferers, treatments that clear these plaques have no effect on the symptoms of the disease. And treatments that block the beta-amyloid proteins that make up the plaques, or the tau proteins that develop within neurons of people with Alzheimer鈥檚, also have had little impact.
Perhaps that鈥檚 because the disease is triggered by something completely different. Last year, team at the University of Leipzig in Germany examined tissue taken from healthy brains and from the brains of those who had Alzheimer鈥檚 at the time of death, or who showed signs of being about to develop the disease. They found that about 10 per cent of neurons in the brains of healthy people contained more than two sets of chromosomes, a condition known as hyperploidy. The finding is astonishing because all cells in the human body 鈥� other than sperm and eggs 鈥� are supposed to contain just two sets of chromosomes.
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More importantly, in the period just before Alzheimer鈥檚 develops and in the early stages of the disease, Arendt and colleagues found that hyperploid cells double in number. Then, in the final stage of Alzheimer鈥檚, most of these unusual cells disappear altogether 鈥� of the brain cells lost, 90 per cent are hyperploid (see diagram) (American Journal of Pathology, ).
But the question remained: are the extra hyperploid cells in Alzheimer鈥檚 patients a result of errors in fetal brain development or do they develop anew in adults with Alzheimer鈥檚 disease? If they are new, preventing them from forming may suggest a treatment.
Arendt鈥檚 team is preparing to publish research in which they conclude that the doomed hyperploid cells are more likely to be generated by the adult brain as part of the disease process. 鈥淲hat it tells us is that these cells are not preformed, which points to them being part of the Alzheimer鈥檚 disease pathology,鈥� Arendt told 快猫短视频.
The implication is that preventing the development of hyperploid cells could be a key to successful treatment.
In the latest research on normal brains, Arendt wanted to find out if the abnormal hyperploid cells were confined to the areas of the brain that are typically hardest hit in Alzheimer鈥檚, or whether they are spread everywhere. The short answer, he says, is that they are dispersed evenly throughout a healthy brain, whereas they are confined narrowly to the 鈥渢hinking鈥� and 鈥渕emory鈥� regions of the Alzheimer鈥檚 brain. These areas are hit hard by the disease.
鈥淗yperploid cells are confined to the 鈥榯hinking鈥� and 鈥榤emory鈥� regions of the Alzheimer鈥檚 brain鈥�
Arendt has also found crucial differences between hyperploid cells in normal people and those with Alzheimer鈥檚. It is still unclear how or why these cells form in healthy brains, but those in the diseased brains appear to be the result of faltering attempts at cell replication 鈥� a process that tends to be rare in the brain. During replication, the chromosomes within a cell duplicate before the cell itself divides, with each daughter cell taking with it a full set of chromosomes. But the cells replicating in the brains of people with Alzheimer鈥檚 fail to divide after the chromosomes duplicate 鈥� leaving parts of the brain with abnormally high numbers of hyperploid cells.
Already, a research team in Spain is working out why, by studying naturally hyperploid retinal neurons in embryonic chicks. Jos茅 Mar铆a Frade and his colleagues at the Cajal Institute in Madrid found that during natural cell division a growth-promoting molecule called nerve growth factor (NGF) activates a cell surface molecule called the p75 neurotrophin receptor (p75NTR). Crucially, they found that another substance called brain derived neurotrophic factor, or BDNF, prevents the cells dividing, leaving them locked in a hyperploid state. Such abnormal cells would tend to self-destruct, but BDNF apparently blocks any suicide attempts.
Frade says that the concentration of BDNF in the brains of people with Alzheimer鈥檚 drops just before the hyperploid cells begin to die. So is BDNF the chemical that keeps these 鈥渉obbled鈥� cells going for as long as possible, explaining why Alzheimer鈥檚 is such a long, drawn-out disease?
鈥淎t present, we鈥檙e actively working on this hypothesis,鈥� says Frade. Indeed, a study in 2009 found that injecting more BDNF into the brains of rodents and primates with Alzheimer鈥檚-like diseases blocked cell death and improved the animals鈥� memory.
Even if BDNF can alleviate symptoms of Alzheimer鈥檚 by preventing the death of hyperploid cells, it is still unclear why the heightened cell replication that causes the cells to form occurs in the first place. This may be where mainstream theories of what causes the disease come into play.
Beta-amyloid, long associated with the disease, can bind to and activate the cell surface molecule p75NTR that kicks in at the early stage of cell division 鈥� so beta-amyloid may accelerate and spread the order for cells to start the replication process. BDNF may then step in to prevent the cells completing the division process, leaving them in a hyperploid state. Ultimately, production of BDNF begins to wane and all hyperploid cells are free to self-destruct, drastically reducing the number of neurons in severe cases of Alzheimer鈥檚.
Arendt is exploring whether the cell-cycle activation process can be blocked before the early stages of Alzheimer鈥檚, to stop generation of the abnormal cells. 鈥淲e鈥檙e hoping to develop a therapy,鈥� says Arendt. 鈥淲e have interesting results, but they鈥檝e been submitted for publication, so we can鈥檛 talk about them yet.鈥�
Other Alzheimer鈥檚 researchers have responded positively to Arendt鈥檚 work. 鈥淎rendt鈥檚 paper from last year is required reading in my lab,鈥� says of Rutgers University in Piscataway. New Jersey, who reported as far back as 2001 that hyperploid cells died in Alzheimer鈥檚 patients (Journal of Neuroscience, vol 21, p 2661). His finding was largely ignored at the time. 鈥淚t is still correlation, not causality, but there is almost no other way to interpret the data other than the way Arendt lays it out,鈥� he says. 鈥淚 think this is a stunning piece of work.鈥�
Mind-expanding slugs
Nifty detective work has uncovered hyperploid cells elsewhere in the animal kingdom. Slugs have giant neurons, precisely because the cells are hyperploid, says and his colleagues at Tokushima Bunri University in Sanuki, Japan.
Matsuo鈥檚 team took identically sized slugs and divided them into two groups, starving one group and giving the other as much food as they could eat. The brains of the overfed slugs grew twice as large as the unfed group鈥檚, and contained almost double the amount of DNA, but still had the same number of neurons (Journal of Neuroscience, ).
Matsuo says that the extra DNA may enable each cell to produce more vital brain proteins and signalling molecules without having to waste energy generating new cells.
Jos茅 Mar铆a Frade of the Cajal Institute in Madrid, who is studying hyperploidy in mammals, says that Matsuo鈥檚 work could have implications for studying hyperploidy in Alzheimer鈥檚 patients. 鈥淭hey could undergo shape changes altering their function and disrupting connections,鈥� he says.
Frade also says that the slugs might provide useful research tools in Alzheimer鈥檚 disease, to test drugs that stop cells multiplying their DNA.
