Alzheimer’s disease: how could stem cells help?
Alzheimer’s disease is the most common cause of dementia. It is a complex disease that affects nerve cells in many parts of the brain, making effective treatment very challenging. Can stem cell research help us tackle this challenge in the future?
Alzheimer’s disease (AD) is the leading cause of dementia. People affected by AD commonly experience memory loss, confusion and mood swings.
The cause of AD is still unknown, but several theories focus on two proteins, called ‘amyloid beta’ and ‘tau’, which are found in deteriorating areas of an AD brain.
Clumps of amyloid beta proteins form plaques that may prevent neurons from sending signals properly.
Tau protein is important for normal cell function, but researchers think that when tau gets gnarled up into ‘tau tangles’ it prevents neurons from getting nutrition.
There is currently no cure for AD.
AD brains make smaller amounts of neurotrophins, proteins that help neurons grow and survive. Studies are examining ways to produce more neurotrophins in AD patient brains.
No stem cell treatments are currently approved for AD. Positive effects have been seen with neural stem cell transplants given to mice with a disease similar to AD, but researchers are still studying what these stem cells are doing and how they might help repair the brain.
Researchers are using induced pluripotent stem cells to grow neurons that have the same genetic background as people affected by AD so they can study the disease.
There are many different neurons throughout the brain that are destroyed by AD, making each case unique and very difficult to treat.
Successful stem cell treatments will need to distribute cells to damaged areas throughout the brain, make the correct types of neurons and other brain cells, correctly ‘wire’ new neurons into existing neuron networks, and, above all, be safe (e.g. not cause cancer or other complications).
If stem cells treatments are eventually developed for AD, these treatments do not stop the cause of AD. Meaning treatments may not last and people could suffer relapses.
Alzheimer’s disease is the most common cause of dementia. The first signs of Alzheimer’s often include lapses in memory or struggling to find the right words. Over time, symptoms such as confusion, mood swings or memory loss develop and become increasingly severe.
The cause of the disease is still unclear, but researchers have found that people affected by Alzheimer’s have an abnormal build-up of certain proteins in the brain. One of these proteins, called amyloid beta, clumps together to form ‘plaques’. Another, known as tau, gets twisted into protein ‘tangles’. Scientists are still exploring whether these changes in the brain lead to the symptoms of Alzheimer’s. One theory is that plaques prevent nerve cells inside the brain from communicating properly. Tangles may make it difficult for the cells to get the nutrients they need. Whatever the exact processes involved, it is clear that as Alzheimer’s develops certain nerve cells die. Increasing numbers of nerve cells, also called neurons, are lost as the disease progresses. For this reason, Alzheimer’s is known as a neurodegenerative disease.
Estimates suggest that up to around 1.5% of people aged 65-69 and around 25-30% of 90-year-olds have Alzheimer’s disease. Although the exact cause is not known, a number of risk factors have been linked to the disease. The biggest of these is aging. Women are more likely to be affected than men,and genetics (i.e. family history) also play an important role, alongside many other factors.
There is currently no cure for Alzheimer’s disease. Drugs are available that can help with some of the symptoms temporarily, for example by improving memory or the ability to manage everyday tasks. Most of these drugs belong to a class called cholinesterase inhibitors (e.g. Aricept, Exelon, Reminyl). They can help prevent the breakdown of a natural substance in the brain called acetylcholine, which carries signals between neurons. However, there are no drugs that delay or halt the loss of neurons. Over the last two decades extensive research and drug development efforts have identified potential new drugs for clearing the build-up of amyloid protein in the brain. Unfortunately large clinical trials with these substances have failed, raising new questions about how the disease is represented and understood in the laboratory. Research to date has mainly been carried out on mice with Alzheimer’s-like conditions, known as mouse ‘models’ of the disease. Stem cells may play a role in providing new disease models that enable researchers to study the disease in human cells, and eventually to develop new treatments.
No stem cell treatments for Alzheimer’s disease are yet available. Many different types of neurons in all parts of the brain are affected by the disease. This poses a complex problem if we want to replace the damaged brain cells. For example, one approach might be to transplant neural stem cells (a type of stem cell found in the brain) into the brain of an Alzheimer’s patient in the hope that they would make new, healthy neurons. But even if healthy, working neural stem cells were available and could be transplanted safely, they would have to achieve several difficult tasks before any therapeutic benefits might be seen:
- travel into the multiple areas of the brain where damage has occurred
- produce the many different types of neurons needed to replace the damaged or lost cells
- do this in a way that enables the new neurons to integrate effectively into the brain, making connections to replace the lost parts of a complex network
Despite these significant challenges, scientists have been actively engaged in research on stem cell transplants in mice and studies have shown some benefits. This is very early stage research and there are still many questions to be answered. For example, many scientists are concerned that the brain may lack the ability to integrate new neurons properly once Alzheimer’s has taken hold. Another concern is that transplanted stem cells might be damaged by the amyloid and tau proteins building up in the brain, meaning a transplant could have only a temporary effect Much more work is needed before the findings could be applied to developing a therapy for human patients.
Another possible approach to stem cell therapies might be to use certain types of stem cells to deliver proteins called neurotrophins to the brain. In the healthy brain, neurotrophins support the growth and survival of neurons, but in Alzheimer’s patients neurotrophin production is low. Neural stem cells produce neurotrophins and so might offer a route to solving this problem. To test this theory, scientists bred mice with the key symptoms and characteristics of Alzheimer’s, such as memory impairment. They then injected neural stem cells into the brains of the mice and observed some improvement in memory. Further studies are now taking place to understand this effect, but the approach has not yet been tested in human patients.
Many scientists believe that Alzheimer’s patients will benefit from stem cells in a different way before the development of potential cell transplantation therapies. By using stem cells derived from Alzheimer patients to grow large numbers of brain cells in the lab, scientists can study the disease and search for new drugs.
A day in the life of a dementia researcher. Scientist Selina Wray takes Alzheimer’s Research UK through her day.
Current research is using a type of stem cell called induced pluripotent stem (iPS) cells to study Alzheimer’s disease. These lab-grown stem cells are made by ‘reprogramming’ specialised cells such as skin cells. The resulting iPS cells can produce all the different types of cells in the body. This means they could act as a source of cells that are otherwise difficult to obtain, such as the neurons found in the brain.
Scientists have recently used iPS technology to grow neurons in the lab that show some of the key features of Alzheimer’s disease. The researchers took skin cells from Alzheimer’s patients and reprogrammed them to make iPS cells. They then developed a method for growing neurons from these iPS cells in a dish. The lab-grown neurons release the beta amyloid protein that forms plaques in patients’ brains. Similarly, scientists have used iPS neurons to study the build up of tau protein, which forms the tangles in patients’ brains in Alzheimer’s Disease. This gives scientists a valuable opportunity to study neurons similar to those affected by the disease in the brain, e.g. to gain a better understanding of how and why protein plaques are formed, and to search for and test new drugs.
This approach holds great promise because it has the potential to address a key problem in understanding and eventually curing Alzheimer’s disease: the disease can vary significantly from one patient to the next. It therefore seems likely that different patients may have different underlying causes. Each cause may need its own treatment and these differences cannot always be studied effectively in animals. If neurons grown from patient-derived stem cells in the lab show the features of Alzheimer’s, then coupling cell biology studies to the patient’s clinical symptoms and experiences could provide key knowledge about how the disease works.
Although some companies may claim to offer stem cell treatments for Alzheimer’s disease, these are outside the approved and carefully controlled process of clinical trials. There have been reports of Phase I (i.e. trials to assess safety but not whether a potential treatment works) clinical trials in the US using mesenchymal stem cells for Alzheimer's disease. Caution is advised until the results of these trials are published as there are queries about the scientific rationale of this strategy. Currently, no proven, safe and effective stem cell treatment for this disease is yet available. However, scientists are already utilizing stem cell technology to carry out rigorous studies on the causes and effects of Alzheimer’s disease, and expect their findings will play an important role in finding new drugs and perhaps also cell-based therapies in the future.
Lead image represents the loss of connection between neurons in the brain with Alzheimers, courtesy of the National Institute on Aging/National Institutes of Health. Animated image created by 7mike5000 from Inside the Brain: Unraveling the Mystery of Alzheimer's Disease by the National Institute on Aging. High magnification image of nerve cells called astrocytes by Nephron. All remaining images courtesy of the National Institute on Aging/National Institutes of Health.