July 13, 2021

Stem cell Alzheimer’s disease research

Stem cell Alzheimer's disease research


Could stem cell Alzheimer’s Disease (AD) research provide a potential path to future treatment or preventative measures?

The goal of today’s post is to provide a review of the state of the field in this area including possible approaches and challenges. 

Stem cell Alzheimer's disease research
Stained section of brain from an Alzheimer’s Disease patient. Amyloid plaque (Red) and phosphorylated Tau (Red and blue) in AD
Image provided by Dr. Jose Luna. National Dementia Biobank. Universidad Autónoma de México.

What is Alzheimer’s Disease and how does it affect the brain?

AD  is a terrifying and fatal neurodegenerative disease that, according to the Alzheimer’s Association, accounts for 60-80% of dementia cases. It kills neurons and disrupts the communication among neural networks, affecting the patient’s memory and, gradually, the ability to function unassisted. The consequences of this disease can be overwhelming and elicit strong emotions in loved ones. Unfortunately, there is no cure to Alzheimer’s, but there are treatments and medications that can modestly suppress or delay its symptoms. The hope is that in coming years much more effective treatment or preventative measures will be discovered. Here, I will discuss different lines of clinical research on potential stem cell therapies for Alzheimer’s Disease. 

As the most common cause of dementia, Alzheimer’s disrupts memory, thinking, and behavior. The cause of the disease is still unclear, but there are several known risk factors, including, according to the NHS, increasing age, genetics, untreated depression, and conditions related to cardiovascular disease. 

Mechanisms versus compensatory events in AD

The physical changes caused by AD occur in the brain, where there are networks of neurons and associated cells that communicate, metabolize, and regenerate. Plaques, which are clumps of amyloid-beta proteins, and neurofibrillary tangles, which are accumulations of twisted threads of tau proteins, are two significant features in a brain with Alzheimer’s. See stained image of the brain of an Alzheimer’s patient for example of plaque structure.

Though it is unclear whether plaques and tangles are the sole causes or reactions of the disease, there is a consistent increase in them in the brain as the disease advances. In the initial stages of AD, neuronal connections associated with memory, learning, and thinking in the entorhinal cortex and hippocampus are destroyed by the accumulation of plaques and tangles, this build up beginning even years before AD symptoms arise. This initial delay in symptoms is thought to be due to the incredible capacity of the brain to compensate for damage.

In the moderate stages of AD, there is increasing spread of plaques and tangles to other sections of the brain, including the cerebral cortex, and the patient can experience troubles in verbal communication and cognitive awareness.

By the severe stages, the majority of the cortex is affected by the plaques and tangles, and brain atrophy, the death and loss of neurons and their connections, can lead to considerable shrinking in brain volume. At this period, Alzheimer’s patients are unable to function independently, recognize family, and sometimes even to speak.

Stem Cell Alzheimer’s Research

Stem cells are one possible treatment approach to Alzheimer’s and there is a great deal of research in this area. Stem cell Alzheimer’s Disease research is broken into two main categories: disease modeling and potential treatment. 

Although there is currently no FDA-approved stem cell therapy to treat AD, there has been potentially promising research done on animal models.

There are two main proposed mechanisms by which stem cells or other cellular therapies might help AD.

First, in some cases stem cells might be able to replace dead or damaged brain cells. The second mechanism is indirect where stem cells or their differentiated progeny secrete factors that reduce harmful inflammation in the brain and promote regeneration via existing brain cells. In the first possible scenario, since entirely new brain cells or segments of brain tissue would be generated, while such cells would not be able to store or mediate past memories, they may improve memory moving forward.

The most common stem cells used for this research have been embryonic stem cells (ESCs), mesenchymal stromal/stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). Transplant studies based on ESCs have shown improvements in spatial memory and performance in rats with AD, but the pluripotency of ESCs poses a risk of uncontrolled differentiation and, thus, tumor growth. MSCs have reportedly reduced amyloid-beta plaques and generated anti-inflammatory and immunomodulatory effects in rodent AD models. NSCs have a paracrine effect that has been shown to promote neurogenesis (the formation of new neurons) and better cognitive function, and reduce neuroinflammation in rodent AD models. Researchers have used iPSCs to derive neurons similar to the neurons of AD patients and study the effects and origins of the plaques and tangles.

Model limitations and disease complexity

But, it is important to be aware that rodent modeling of AD is a limited perspective on how the disease progresses in humans. Because of the significant anatomical differences, it is not sufficient to clinically implement stem cells in human patients based on results generated by rodent models. In addition, mouse models have lacked representing the sporadic form of AD that most people have.

The complexity of Alzheimer’s disease also presents challenges to its study and possible treatment. Because AD is a progressive disease that exacerbates over time, early detection biomarkers are being studied and are promising in regards to facilitating the disease before the severe stages of AD. There is still lots of research to be done in regards to several aspects of Alzheimer’s that can advance its treatment and prevention. Thus, understanding the cause of the disease is a crucial element that can also be supported by the study of stem cell models.  

The Aduhelm case & development of stem cell therapy for Alzheimer’s

A recent development this summer illustrates the broader challenges of trying to develop drugs for Alzheimer’s. This article in the Washington Post does a nice job covering the news that the FDA allowed the first accelerated approval of an Alzheimer’s drug, Aduhelm, prompting controversy including over the underlying cause of the disease.

Historically, the amyloid hypothesis held that plaques, or clumps of amyloid beta, are the major causes of AD. However, researchers are now mostly concurring that the connection between amyloid beta and AD is more complex. Though Aduhelm has been shown to remove plaque and slow down cognitive decline, the controversy is centered on its fast approval even after an FDA advisory panel concluded there was a lack of sufficient clinical evidence. Several experts have opposing views on the FDA’s decision for this new drug, but some think that Aduhelm may provide a modest clinical benefit to certain patient subgroups.

There seems to be a growing consensus that only targeting amyloid plaques will not be adequate in the treatment of AD. We will have to see how the stem cell clinical research in this area proceeds to know if a stem cell approach might provide additional concrete options.

References



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