Research in Alzheimer’s Disease: Hope for Curative Treatment

In Advances in Alzheimer’s disease, scientists discuss research which would hopefully lead to the development of drugs that would cure Alzheimer’s disease. Alzheimer’s disease makes a person forgetful and as the condition progresses, it affects other mental functions as well. There are several drugs that are available for its treatment. However, these drugs can only slow the progression of Alzheimer’s disease but cannot cure it. They are mostly effective in early stages of Alzheimer’s disease. In late stage Alzheimer’s, the affected individual is usually completely dependent on the caregivers.

Drugs that are currently used in Alzheimer’s disease affect neurotransmission, that is, the signalling between nerves. When information from one nerve has to be passed to another, a substance called a neurotransmitter is released from the first nerve which docks on the next nerve and conveys the signal. Since neurotransmission via acetylcholine is reduced in Alzheimer’s disease, drugs that enhance this neurotransmission which include galantamine, donepezil and rivastigmine are beneficial in the treatment of Alzheimer’s disease. Another drug memantine acts via another signalling pathway called the glutamate signalling.

Several other drugs which affect neurotransmission are also being evaluated for the treatment of Alzheimer’s disease. But that is not all. New strategies are being explored which would hopefully lead to the development of drugs that could even cure Alzheimer’s disease. The review article by Justin Davis and Robin Couch highlights just this, and is summarised below.

Drugs for Alzheimer’s disease under investigation act through several mechanisms which include the following:

Inhibition of the Enzymes β Secretase and ɣ Secretase

Patients with Alzheimer’s disease have accumulations of amyloid-β peptides in the brain. These are generated from another protein through the action of two enzymes β secretase and ɣ secretase. Thus, drugs that inhibit these enzymes could possibly prevent the accumulation of amyloid-β peptides in the brain and play a role in the treatment of Alzheimer’s disease.

However, drugs that completely inhibited ɣ secretase were associated with serious side effects and could not be developed as anti-Alzheimer’s drugs. Therefore, drugs that bring about modulation of ɣ secretase instead of complete inhibition are being evaluated instead. Inhibitors of β secretase have comparatively fared better in clinical trials. However, one of these drugs turned out to be toxic to the liver and its development had to be discontinued.

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Vaccination against Alzheimer’s Disease

Another approach to develop treatment for Alzheimer’s disease is by vaccination. A vaccine introduces some components of the β amyloid peptide into the body which is likely to stimulate the body to produce antibodies. These antibodies will probably act against the β amyloid deposits in the brain, and hopefully cure the disease. It is necessary to develop a product that does not produce brain inflammation, and thereby result in further brain damage.

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Instead of a vaccine that produces antibody response, it has been suggested that direct injection of antibodies that will act against the β amyloid protein, may be an effective treatment. However, current research using this approach has yet to yield successful results.

Inhibition of Hyperphosphorylation of tau

Another important pathology seen in Alzheimer’s disease is the formation of neurofibrillary tangles in the brain. These are composed of a hyperphosphorylated form of a protein called tau. Normal tau associates with microtubules, which play an important role in the structure and function of the nerves, while hyperphosphorylated tau contributes to neurofibrillary tangles and deposits in nerves. Hyperphosphorylation is mediated by several enzymes called kinases. This has encouraged research in developing:

• Inhibitors of kinases, which would prevent hyperphosphoryation of tau and thereby allow normal functioning of tau. Inhibition of these enzymes could result in some other unknown benefits as well.
• Inhibitors of tau aggregation.

Drugs that stabilize microtubules and thereby restore the structure and function of neurons could also be beneficial.

Other Treatments that are also being investigated include:

• Antioxidants to reduce oxidative stress and prevent damage to nerves.
• Drugs to induce ketosis, so that the brain can use ketones as a source of energy instead of glucose. There are problems in using glucose by the brain in patients with Alzheimer’s disease. Therefore, alternate sources of energy may be beneficial. Medications providing medium chain fatty acid has also been tried out.
• Drugs that suppress inflammation, since inflammation may be a part of Alzheimer’s disease.
• Drugs that reduce neurodegeneration. In Alzheimer’s disease, certain neurons get destroyed. Neurotrophins are substances that promote growth and survival of neurons. Studies are therefore directed towards finding methods to deliver neurotrophins to the brain, or to increase the production of neurotrophins by the body. Certain phosphodiesterase inhibitors ultimately increase the level of neurotrophins and therefore are being investigated for the treatment of Alzheimer’s disease.
• Drugs that act on several other targets that include HMG-CoA reductase, peroxisomes, angiotensin receptors, heparanase matrix metalloproteinase, hormone supplementation and vitamin supplementation.

The diverse approaches to developing drugs for Alzheimer’s disease will hopefully culminate into at least a few drugs to cure this disabling disease.

Reference:

Davis, J. and Couch, R. (2014) Strategizing the Development of Alzheimer’s Therapeutics. Advances in Alzheimer's disease, 3, 107-127. doi: 10.4236/aad.2014.33011.

Source-Medindia