The memory and learning problems experienced by Alzheimer鈥檚 patients might one day be reversible by re-awakening key brain cells scientists thought had died, say US researchers.
The team, led by Jonathan Cooper, now at King鈥檚 College London, and William Mobley at the University of Stanford, say they can arouse apparently dead cells with the help of a chemical messenger called nerve growth factor, or NGF.
A separate team in San Diego recently began transplanting skin cells modified to make NGF into the brains of patients in the early stages of the disease, in the hope of preventing further cognitive decline. But the new findings suggest the transplants could potentially reverse the symptoms.
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The new work was carried out in mice genetically modified to develop an equivalent of Alzheimer鈥檚 at an early age. Cholinergic cells in the basal forebrains of these mice shrink as the disease progresses, mimicking the process in human patients, and causing the loss in memory and learning function. The discovery that the cells can be resurrected is 鈥渧ery exciting,鈥� says Cooper. 鈥淚t鈥檚 an interesting new thought.鈥�
Richard Harvey, director of research at the UK鈥檚 Alzeimer鈥檚 Society says: 鈥淲e see it as a promising step forward, but are concerned about safety [of the transplants]. It鈥檚 a high-tech treatment, and it鈥檚 difficult to see how you could use it in the millions of Alzheimer鈥檚 patients.鈥�
Road block
The mice were genetically engineered to have the equivalent of Down鈥檚 syndrome. Although many people with Down鈥檚 have a near-normal life expectancy, most of them develop Alzheimer鈥檚 symptoms at a relatively young age. This meant the mouse strain was an ideal model to study the disease.
In people with Alzheimer鈥檚 and Down鈥檚, it is the loss of the cholinergic cells in the basal forebrain and their connections to a brain region called the hippocampus that contributes to the age-related decline in learning and memory in both conditions. Mice lacking NGF have similar symptoms, so Cooper鈥檚 team decided to find out more.
They found that the Down鈥檚 mice seemed to lose the key brain cells, as expected. However, surprisingly, their brains still made NGF, they report in the journal Proceedings of the National Academy of Sciences .
NGF is normally packaged up and transported from its manufacture site in the hippocampus to these key cells. The Down鈥檚 mice seemed to have some sort of 鈥渞oad block鈥� preventing NGF from arriving at its destination.
鈥淟iving dead鈥�
Cooper decided to bypass this blockade by injecting NGF into the fluid-filled spaces, or ventricles, lying next to these cells. To his surprise, NGF not only restored the shape and size of the neurons, but also reversed their reduction in numbers, even in elderly mice with the worst symptoms.
鈥淓ven in the very old and very sick mice, we can do this,鈥� says Cooper.
He thinks that these cells do not in fact die, but instead switch off some of their genes, including the ones researchers use to detect them. 鈥淚n some sense, they are the living dead,鈥� he says.
The team now plan to find out whether this reversal has an effect on the mice鈥檚 behaviour. They are also trying to find out exactly what causes the roadblock in NGF transport.
Getting NGF into the brains of patients is tricky, so understanding what goes wrong might provide new therapeutic targets. But Cooper warns that he can鈥檛 yet predict what the outcome in humans will be. 鈥淚t鈥檚 far too early to tell,鈥� he says.