Alzheimer's disease - Old friends and new promises

Having trouble remembering a name or a word, or occasionally not being able to think clearly, can be normal parts of life. But when these problems start to interfere with one’s ability to perform basic daily tasks such as working or preparing meals, they could be signs of a condition known as dementia.

Dementia is not a specific disease – rather it is a general term for a decline in mental ability that is severe enough to interfere with daily life. Because the condition has a very wide range of symptoms, it is very difficult to describe or classify dementia-related diseases. Several factors can raise one’s risk for developing dementia, including aging, smoking, uncontrolled diabetes, high blood pressure, poor dietary habits, and alcohol abuse. Studies also suggest that some people are genetically predisposed to develop the condition – in other words, people who have family members that suffered from dementia are at greater risk of developing the condition themselves.

What is frightening is that the number of cases of dementia is steadily on the increase all over the world, but particularly in developing countries. The majority of countries where increases have been recorded are in South America and East Asia. The increase in the number of recorded cases of dementia can be attributed to the fact that people in these countries are increasingly living longer. A drastic increase in the number of cases is also projected for countries in sub-Saharan and North Africa.

Alzheimer's disease is the most prevalent form of dementia and accounts for roughly 60–80% of dementia cases. It is an irreversible, progressive brain disorder that slowly destroys memory, thinking skills, and eventually the ability to carry out the most basic tasks of everyday life. On average, a person with Alzheimer's lives for four to eight years after diagnosis, but they can live as long as 20 years, depending on other factors. The disease currently affects more than 35  million people worldwide, and the World Health Organisation (WHO) predicts that this number will double every 20 years. This means that by the end of 2050 there will be around 150,4  million people suffering from Alzheimer’s disease.  

Despite the fact that increasing age is the greatest known risk factor, and the majority of people who suffer from the disease are older than 65 years of age, Alzheimer’s disease is not a normal part of aging. It is also not an illness that only affects the elderly. Early-onset Alzheimer’s can affect people who are in their 40s and 50s.

Prof Vanessa Steenkamp, who currently heads the Phytomedicine Unit in the Department of Pharmacology at the University of Pretoria (UP), is involved in research to obtain safer and more efficacious treatments for Alzheimer’s disease. Although there is currently no cure, it is possible to treat the symptoms of the disease. These treatments can temporarily slow the onset of dementia symptoms and improve quality of life.

Prof Steenkamp explains that in order to understand how it can be treated it is important to understand how the disease affects the brain. The two main sections in the brain affected by Alzheimer’s disease are the cerebral cortex, which is the part of the brain responsible for language and information processing, and the hippocampus, which is critical for the formation of new memories. This is why one of the most common problems encountered in Alzheimer’s patients is that they are able to clearly remember events that happened a long time ago, but they are unable to remember something that happened the previous day.

Alzheimer's disease leads to the death of nerve cells and general tissue loss throughout the brain. Over time, the brain shrinks significantly, affecting nearly all its functions. The cerebral cortex shrivels up and in the process causes massive damage to the areas involved in thinking, planning and remembering. The shrinkage is especially severe in the hippocampus, while the ventricles (fluid-filled spaces in the brain) fill up with cerebral spinal fluid and grow larger as the disease progresses.

Prof Steenkamp says that another very important area to look at when doing research on Alzheimer’s is the formation of plaques and tangles in the brain. Plaques are abnormal clusters of protein fragments called beta-amyloids that build up between neurons in the brain and then become very hard. It is interesting to note that we actually all have these plaques in our bodies and brains, but in a healthy person, the body is able to break them down and eliminate them from the system. Tangles in turn are knots that form around the microtubules in the brain, making them hard and eventually causing them to die. Microtubules are microscopic tubular structures that are responsible for transporting micronutrients in the brain, so when they die off the brain is effectively starved of these essential nutrients. As the disease progresses, the area in which these plaques and tangles form increases. 

Prof Steenkamp says that research has shown that Alzheimer’s patients have very low levels of acetylcholine, which is a compound that occurs throughout the nervous system where it functions as a neurotransmitter, and high concentrations of the enzyme cholinesterase, which is an enzyme that stimulates the formation of neural tangles in the brain. 

One of the areas that Prof Steenkamp and her team are currently working in is cholinesterase inhibitors. A cholinesterase inhibitor is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. These are the drugs that are most frequently used to treat Alzheimer’s disease today and they can delay the worsening of symptoms for up to six to twelve months for about half of the people that take them. Although cholinesterase inhibitors are generally well tolerated, side-effects do occur and include nausea, vomiting and loss of appetite.

Two cholinesterase inhibitors that are currently widely used to treat Alzheimer’s patients are Donepezil and Galantamine. The latter is an alkaloid that is obtained from the bulbs and flowers of Galanthus caucasicus, commonly known as the Caucasian snowdrop, which is a plant used in traditional medicine to treat memory loss. The development of treatments from plants is of particular interest to Prof Steenkamp, as the field of Phytomedicine that she specialises in is concerned with the development of medications from plants.

The team at the UP Phytomedicine Unit are also looking into the use of herbal remedies for the treatment of Alzheimer’s. Prof Steenkamp says that herbal remedies are already widely used for treatment and that the reasons people give for preferring these treatments are that they generally perceive them to be safer and better. In some cases, however, people turn to herbal remedies out of sheer desperation as they are well aware that conventional medicine can only delay the inevitable progression of this devastating disease, and are willing to try anything that can potentially help them. Cost, cultural beliefs and accessibility do, of course, also contribute to a person’s choice to opt for herbal remedies rather than the conventional treatments available on the market.

The Phytomedicine Unit’s investigations into traditional remedies have already led to the isolation of new compounds with promising activity. Furthermore, structure–activity-guided analysis has allowed for the synthesis of compounds that are similar to Donepezil (the most widely used medication for the treatment of Alzheimer’s), which have shown promise in in vitro assays. The structure–activity relationship (SAR) that is determined through structure–activity-guided analysis indicates the relationship between the chemical or 3D structure of a molecule and its biological activity. This in turn allows researchers to modify the effect or the potency of a bioactive compound (typically a drug) by changing its chemical structure. Using chemical synthesis, new chemical groups can be inserted into the biomedical compound and the modifications can be tested for their biological effects. Compounds that might have a multi-target action against cholinesterase and β-secretase are currently being synthesised at the Unit.

Prof Steenkamp and her team are working hard to find better ways to treat the disease, delay its onset, and even prevent it from developing in the first place.

Researchers

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  Professor Vanessa Steenkamp

  Professor Vanessa Steenkamp is a medical scientist who is registered with the Health Professions Council of South Africa, and has dual registration as a biological scientist and toxicologist with the South African Council for Natural Scientific Professions.
  
  She completed her first two postgraduate degrees – BSc (Hons) and MSc – at the University of Pretoria (UP) and completed her PhD at the University of the Witwatersrand, where she worked as a researcher and lecturer. After 10 years, she returned to UP and has been doing research and lecturing at the University for 23 years. Prof Steenkamp says that UP has a culture in which she has been able to cultivate and curate a vast wealth of experience in research. She has great appreciation for her colleagues with whom she has forged great collaborations and collectively promoted and extended expertise to other universities and institutions.
  
  Within the University, Prof Steenkamp has a long-standing collaboration with two groups in the Department of Chemistry. She works with Prof Vinesh Maharaj on the isolation and identification of bioactive phytochemicals in traditional herbal remedies, and with Prof Darren Riley on the synthesis of new compounds based on the backbone of drugs originating from plants, in the hope of synthesising new compounds with better efficacy.
  
  Prof Steenkamp heads UP’s Phytopharmacology Unit, which specialises in the development of drugs to treat dementia, especially Alzheimer’s and Parkinson’s diseases; and promotes wound healing, antimicrobial activity and anti-cancer activity. Regarding the latter, the unit is investigating genetic polymorphisms associated with anti-cancer drug efficacy. The goal of precision medicine is to improve the clinical outcomes of patients by considering their individual variability. Pharmacogenomics aims to understand how genetic variants influence drug efficacy and toxicity, and is therefore an important tool for precision medicine as it can guide the clinical management of patients based on their unique genetic make-up.
  Asked if she has begun new research in the past 18 months, Prof Steenkamp says: “All research is new. Once a specific project is completed, new questions arise – this is the cycle of research. We are developing an in vitro neurological model that is more representative of the in vivo situation. This involves differentiation of cells to form neurites. We are also analysing clinical samples to assess genetic polymorphisms and drug efficacy in prostate and breast cancer, which will shed light on why some patients react to treatment and other patients don’t.”
  
  A project that the unit is nearing completion on, and that will be taken further, is determining the cannabinoid profile of cannabis oils sold for medicinal use as well as assessing compliance of these products to South African regulations. “There are concerns as to how safe cannabis use will be ensured, how cannabis dependence and addiction will be prevented, and whether quality control measures will be implemented when it comes to cannabis and cannabis-containing products,” says Prof Steenkamp, who is a steering member of the Cannabis Organisation of the University of Pretoria, which advances the creation and dissemination of knowledge regarding cannabis.
  
  On what the public should know about phytopharmacology, she says: “The use of botanicals is well rooted in medical practice. Ancient doctors methodically collected information about herbs and developed well-defined pharmacopoeias to treat a variety of ailments. More than a quarter of all drugs used today contain active ingredients derived from those same ancient plants.
  
  “In South Africa, traditional healers are the first point of call for most of the population. There is also the belief that herbal remedies are better and safer because they are natural, which is why many people buy products from herbal shops or over the internet. But the public must realise that these herbals contain active compounds that have physiological effects and that could interact with Western medicines. To avoid possible adverse effects, it is important that a patient discloses to their physician that he or she is taking herbal remedies, whether with chronic medication or before medication is prescribed. Furthermore, natural remedies are not always safe, and buying them over the internet or from unregistered producers poses the risk of toxicity.”
  
  The professor says she aspires to contribute to knowledge in her field and ensure that this knowledge has a positive impact on human health and well-being. Her research matters, she adds, because drug discovery and development are among the most important translational science activities that contribute to human health and well-being. “My research seeks to develop drugs to treat diseases for which there is currently no medication. If successful, this will ultimately improve the quality of life of patients with these diseases.”
  
  She advises school learners or undergraduates who are interested in her field to read up about it, make contact with somebody working in the field and to ask lots of questions. “You need to ensure that you are fully satisfied and can make a sound decision as to whether this field is for you,” she says.
  
  Prof Steenkamp’s hobbies are gardening, reading and being in nature. “I believe my research interest flows into my gardening – knowing the uses of different plants as well as propagating them. I read widely on research topics, but also find time to unwind by reading intriguing, factual novels.”
  

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  Alzheimer's disease - Old friends and new promises