Alzheimer's disease
This debilitating disorder causes memory loss, emotional problems and impaired reasoning. It affects one person in 10 over the age of 65 and almost half those over the age of 85.
The abnormalities of Alzheimer's disease can be found in primates, ie humans and monkeys1, and in certain strains of mice2,3,4. Animal studies provide opportunities for understanding how Alzheimer's disease affects the brain, and for studying potential new treatments.
The development of Alzheimer's disease is thought to be associated with the death of certain brain cells (known as cholinergic cells) due to the build-up of an insoluble protein called amyloid-beta (Aß) to form white plaques, and the formation of tangles of a second protein, tau, inside the sufferers' brain cells. Amyloid build-up severely inhibits several genes needed for learning and memory5.
The brain changes of Alzheimer's are controlled by certain genes. For instance, research using genetically modified mice has shown how one particular version of the human APP gene leads to build up of damaging deposits in the brain6. Genetically engineered mice have been made that lack the enzyme that makes amyloid. There are compounds that block the enzyme, and these may be clinically useful if they are safe in humans7,8. By studying GM mice with Alzheimer's, scientists have discovered two more genes involved in the early stages of the disease9.
In 2002 and in 2003 scientists produced new genetically modified mice whose disease resembles the human disease more closely, which will mean that more research can be done in mice rather than monkeys10. There is a hereditary, early-onset form of the disease, which has been replicated by genetically engineering mice. Their study has thrown new light on how the genes work11. Other genetically modified mice have enabled scientists to study the plaques and tau tangles in more detail12.
Mice that were genetically engineered to have Alzheimer's have enabled scientists to show that the Aß enters the brain by riding piggyback on a non-toxic molecule called RAGE, which freely crosses the blood-brain barrier. The cells that form the barrier produce RAGE, and in Alzheimer's mice they overproduce it13.
Studies using radioactive labelling of plaques in transgenic mice have shown that earlier diagnosis, and therefore earlier treatment, may be possible14. Brain cells rarely regenerate, probably because it requires a substance called nerve growth factor, which is present in fetuses but very rare in adults. Giving nerve growth factor to ageing monkeys restored the nerve axons in their brains to levels found in young monkeys15. Early diagnosis might one day be possible: a protein called m266 'draws out' amyloid protein from the brain of mice predisposed to the disease, and could prove clinically useful16.
Alzheimer's disease is associated with accumulation of a type of nerve cells called astrocytes where plaque has been deposited, but it has been uncertain until recently whether this is cause or effect. In 2003 research in Alzheimer's mice showed that the astrocytes migrate there in response to a chemical present in the plaques, which they attempt to degrade17. Treatments that attract more astrocytes might therefore benefit patients.
Boxing and football predisposes to Alzheimer's disease, and research in mice shows that this is causal: mice that received repeated head trauma developed plaque-like deposits faster than mice that suffered a single or no injury18. The bacterium Chlamydia pneumoniae is found at autopsy in the brains of 90% of Alzheimer's patients, and scientist have found that spraying it into the noses of mice caused plaque formation19.
Several animal studies confirm the clinical impression that healthy lifestyles offer a degree of protection. Physical activity – five months use of a running wheel – appears to inhibit brain changes in Alzheimer’s mice, enhancing learning ability and decreasing the deposition of amyloid in the brain20.
Obese people are at higher risk of developing Alzheimer’s, and this finding has been replicated in mice: in two studies, Alzheimer’s mice developed 30–50% less plaque when fed on calorie-restricted or low carbohydrate diets21,22. Aged, genetically engineered mice predisposed to Alzheimer’s disease that were fed the fish oil DHA (docosahexaenoic acid), an omega-3 fatty acid, developed significantly less amyloid protein23. The researchers hope that clinical trials will give similar results. Oxidative processes are associated with Alzheimer's, and mice predisposed to Alzheimer's have more oxidative brain damage than normal mice24. This explains why vitamin E temporarily slows disease progression in some patients.
People with diabetes have an increased incidence of Alzheimer's, and working on genetically engineered mice has shown why this happens25. A remarkable new insight came in 2005 when it was discovered that the brain, as well as the pancreas, produces insulin. This insulin does not affect blood sugar but is vital for the survival of brain cells. Therefore, therapies could be designed that specifically influence the actions of insulin in the brain26.
Several lines of research have led to vaccines that slow down or halt the disease in animals. They work by preventing or reducing formation of fibrils tangles or plaques, or by reducing the amount of them27, 28, 29. Some of these are now being tested in clinical trials.
A clinical trial of an effective Alzheimer’s vaccine had to be halted when it was found to cause brain inflammation in some people. Using a harmless form of the herpes virus, the immune systems of mice have been customised to prevent this while still causing a 20% decline in amyloid levels30.
Alzheimer’s mice had their disease halted or even reversed when injected with anti-beta-amyloid antibodies into an area of the brain called the hippocampus. The amyloid plaques were cleared in three days. The lesions caused by fibrous tangles disappeared two days later. Thirty days later, the researchers found the amyloid plaques had re-emerged but the tangle lesions did not31. Another approach was to vaccinate mice with the amyloid gene rather than the amyloid protein, using a gene gun; this, too, prevented brain inflammation32.
Three types of drug used to treat other diseases have been shown to inhibit plaque formation. One type is the non-steroidal anti-inflammatory drugs (NSAIDs), painkillers that are mainly used to treat rheumatic diseases. Of the 20 most commonly used NSAIDs, eight have successfully lowered amyloid levels in mice, using doses achieveable in humans33. The second drug is lithium, which is used for manic depression34. Some epidemiological studies have suggested that people taking statin drugs to control cholesterol have a reduced incidence of Alzheimer’s, and a mouse study throws light on this: blocking a pathway that controls cholesterol distribution in cells – using a drug not yet licensed for humans – dramatically reduced the number of amyloid plaques in the brains. Some of the treated mice were much better at learning their way through a maze than were untreated mice35.
The fibrils found in the brain of Alzheimer's patients are stabilised and bound by a protein called serum amyloid P component (SAP). In 2002 scientists discovered a compound that prevents the action of SAP and speeds its breakdown by the liver. The drug has already been shown useful in patients with a rare and fatal condition called systemic amyloidosis, and clinical trials in Alzheimer's patients have begun36.
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Research Fields: Cell biology, Genetics, Brain & nervous system, Drugs & toxins, Vaccine development(yes - 5 items)Animals Used: Mouse (knockout/GM)(required - 1 items)
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