ALZHEIMER’S disease wrecks lives. And as people live longer, it will wreck more with every passing year. It also wrecks budgets. In America in 2010, the cost of treating those with dementia was $109 billion. That exceeds the cost of treating those with heart disease or with cancer. The RAND Corporation, a Californian think-tank, reckons this cost will more than double by 2040. A treatment for Alzheimer’s is therefore needed for fiscal as well as humanitarian reasons.
On the face of things, developing one does not look too hard a task. One of the main physical symptoms of the disease is the accumulation in the brain of sticky clumps, or “plaques”. These are composed of protein fragments (known as peptides) called amyloid beta. It has been widely presumed that if the plaques can be removed—or, better, stopped from forming in the first place—the confusion and loss of memory that are the main outward manifestations of Alzheimer’s will be relieved as well. It is just a question of inventing a drug that will do this.
Just…
Trial after trial has failed, to the point where researchers are tearing their hair out. But still they try. A paper published this week in the Proceedings of the National Academy of Science describes yet another attempt. Instead of attacking the peptide directly, Stuart Lipton of the Sanford-Burnham Medical Research Institute, in La Jolla, California, and his colleagues are trying to stop its effects. In doing so, they have characterised in new detail the way the peptide wreaks its damage. Which means that even if their specific approach eventually fails, they will have helped clear a trail through the thickets of plaques which others may be able to follow.
Bad connections
Experimental drugs intended to attack amyloid beta directly have proved disappointing. Last year clinical trials of the two most advanced such drugs did not slow the decline of most patients’ memories—though solanezumab, from Eli Lilly, did yield some positive results in a group of patients whose Alzheimer’s was mild.
A better approach might be pre-emption. Some groups of researchers are therefore testing solanezumab to see if it helps elderly people who show no clinical signs of Alzheimer’s, but whose brain scans reveal abnormal levels of amyloid beta.
Testing drugs in this way—to find out if they can stop a disease from starting—is an ethical minefield because it means experimenting on people who are, to all intents and purposes, healthy. Other such trials are nevertheless happening. Roche, a Swiss drug firm, is working with a large family in Colombia whose members frequently sport a mutation that guarantees anyone carrying it will get the disease. And a consortium of researchers in America, Australia, Britain and Germany is also testing the effect of anti-amyloid drugs on people with Alzheimer’s-inducing mutations.
In these two cases the near-certainty of future problems for the people involved means the ethical dilemma vanishes. But there is no guarantee that, even if these trials work, they will illuminate the wider problem. No one is yet quite clear how closely mutation-induced Alzheimer’s resembles the more common “sporadic” sort. A treatment for the one will not necessarily work for the other.
Dr Lipton and his colleagues are therefore trying instead to explain how amyloid beta does its damage, and how that might be stopped. They started from the observation that the peptide seems to work its havoc particularly on glutamate-sensitive synapses. A synapse is a connection between two neurons, across which they communicate via messenger molecules called neurotransmitters. These come in several varieties, of which glutamate is one.
At normal levels, glutamate supports memory formation. But excess glutamate triggers a cascade of worrisome activity. Previous research has suggested that high levels of the stuff, in combination with hyperactive receptor molecules called eNMDA receptors, might be to blame for the problems of Alzheimer’s.
First, Dr Lipton demonstrated amyloid’s effect on glutamate. He and his colleagues added amyloid beta to cultures of astrocytes, a common type of brain cell that helps support neurons. Dr Lipton found that amyloid beta spurred the astrocytes to release large amounts of glutamate. He also observed the same phenomenon in the brains of living mice.
He then showed the effects of these higher glutamate levels. In a culture of astrocytes and neurons, derived from human stem cells, he measured whether synapses were firing properly. They weren’t. The team saw the rate of signalling from neurons exposed to amyloid beta (and therefore a lot of glutamate) subside significantly. This seemed to be explained by the excess glutamate’s effect on eNMDA receptors. The neurotransmitter made these receptors hyperactive, ushering a flood of calcium ions into the neuron. That, in turn, prompted the creation of toxic levels of nitric oxide, caspace-3 and tangled tau proteins—all three of which have been implicated in the degeneration of synapses.
A drug called memantine (which Dr Lipton was responsible for developing, and which, he admits, “doesn’t work very well”) had only a small effect on the hyperactivity of the receptors. But by combining memantine with a fragment of another drug, nitroglycerine, Dr Lipton had better luck. The memantine delivered the nitroglycerine to the sick neuron; the nitroglycerine then attached itself to eNMDA receptors and dampened their activity. Signalling by the synapses subsequently improved. Dr Lipton’s combined drug, dubbed nitromemantine, also restored the synapses of mice with Alzheimer’s.
All this sounds exciting. But caution is needed. Many Alzheimer’s drugs have seemed to succeed in animals, only to prove ineffective in people. Promising drugs have also been scuttled by safety problems or technical glitches.
Last year, for example, a paper in Science reported that bexarotene, a drug approved for use against skin cancer, boosted the production of ApoE, a protein that clears amyloid beta in mice. But in May another group of researchers, also writing in Science, said they could not replicate this result. And on June 13th Eli Lilly said it would stop the clinical trial of a drug designed to stop the production of amyloid beta. The substance in question had been shown to damage the liver. The road to an actual treatment for Alzheimer’s, then, remains as rocky as ever.
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