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Alzheimer's disease

This debilitating neurological 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, apes and monkeysANCHOR, and in certain strains of miceANCHORANCHORANCHOR. Animal studies and animal experiments provide opportunities for understanding how Alzheimer's disease affects the brain, and for studying potential new treatments.

Pathology

Alzheimer's disease has long been associated with the development of plaques and tangles of fibrous proteins in the brain. Formed from proteins known as amyloid-beta (Aß) and tau protein respectively, these structures have formed the focus of research into treating Alzheimer’s disease. Despite this it is still unclear whether these plaques and tangles are the source of damage or a symptom of something deeper.

Many large pharmaceutical companies have invested in developing treatments to target amyloid plaques, but all have failed in clinical trialsANCHOR. While it seems that some drugs are able to clear the plaques, they do not appear to slow the degeneration of cognitive abilityANCHOR. The tau protein tangles, however, do appear to correlate better with brain function and much modern research is aimed at removing these.

Recently, Alzheimer’s disease has been referred to as ‘Type III diabetes’ as it appears, through animal experiments, to be linked to insulin resistance in brain cells. Research into the effects of alcohol on insulin resistance in the brains of rats led researchers to note that the loss of insulin receptors in brain cells produced symptoms that were very similar to Alzheimer’s diseaseANCHOR. The same effects have also been seen in rats and rabbits that have diabetesANCHOR. Adding insulin to brain tissue from human cadavers has shown different responses depending on whether the person had been affected by Alzheimer’s disease. The healthy brain tissue began to signal and activate in the presence of insulin while the brain tissue with plaques showed little responseANCHOR.

Genetic Aspects

While there are some rare cases of single gene defects resulting in hereditary early-onset Alzheimer’s disease, most cases are due to multiple factors. There have been several genes discovered that are associated with the disease, however most have only a minor effect on a person’s risk factorANCHOR.

Research and animal tests using genetically modified mice has shown how one particular version of the human APP gene leads to build up of damaging deposits in the brainANCHOR. 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 humansANCHORANCHOR. By studying GM mice with Alzheimer's, scientists have discovered two more genes involved in the early stages of the diseaseANCHOR.

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 itANCHOR.

This video demonstrates some of the techniques used to monitor the progress and treatment of mice with Alzheimer-like symptoms.

Current Treatments

The main class of drugs used to treat Alzheimer’s disease are known as cholinesterase inhibitors. These prevent the degradation of the neurotransmitter acetylcholine. The importance of acetylcholine was first noted in 1914 and later research on frogs and horses revealed its use in the bodyANCHOR.

Improving Diagnosis

Studies using radioactive labelling of plaques in transgenic mice have shown that earlier diagnosis, and therefore earlier treatment, may be possibleANCHOR. Brain cells rarely regenerate, probably because it requires a substance called nerve growth factor, which is present in foetuses but very rare in adults. Giving nerve growth factor to ageing monkeys restored the nerve axons in their brains to levels found in young monkeysANCHOR. 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 usefulANCHOR.

Alzheimer's disease is associated with accumulation of a type of cell 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 degradeANCHOR. Treatments that attract more astrocytes might therefore benefit patients.

Lifestyle Issues

Traumatic brain injury 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 injuryANCHOR.

Some reports have found the bacterium Chlamydia pneumoniae in the brains of 90% of Alzheimer's patients at autopsy, although this has been difficult to reliably reproduce in later studiesANCHOR. Scientists have found that spraying it into the noses of mice caused plaque formationANCHOR.

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 brainANCHOR.

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 dietsANCHORANCHOR. 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 proteinANCHOR. 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 miceANCHOR. This explains why vitamin E temporarily slows disease progression in some patients.

Potential Medicines

Some drugs that are 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 achievable in humansANCHOR. Trials in humans have shown conflicting results but a trial of 7000 people showed that taking NSAIDs over two years leads to an 80 per cent decrease in the risk of Alzheimer’s disease. However, NSAIDs are not without side-effects and a large NIH trial had to be suspended part-way through because of theseANCHORANCHOR.

Lithium, which is used for manic depression, has previously been shown to have neuroprotective effects. Mice given lithium for 5 months showed reduced levels of with tau protein tangles in their brainANCHOR. Epidemiological studies have shown that bipolar patients taking lithium have a lower risk of Alzheimer’s disease and small trials have shown that patients with mild cognitive impairment undergo less cognitive decline when taking lithium over 12 monthsANCHOR.

Given the failures of research into the amyloid plaques, new treatments are being developed that focus on breaking down the tau protein tangles. Drugs known as methylthioniniums are going into phase III clinical trials, having shown up to 90% reduction in disease progression over 2 years in phase II trialsANCHOR. These drugs were developed partly based on research with transgenic mouse models of Alzheimer’s disease.

Despite their simplicity relative to humans, fruit flies have formed an important part of understanding the development of tau tangles. The flies can also be altered genetically to produce clearly observable traits when tau tangles form, making them a useful for screening potential new compounds or breaking down the tanglesANCHOR.


References

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