Pluripotent stem cells can treat Alzheimer’s disease

By ANNA CHEN | March 8, 2018

At the University of Washington School of Medicine in Seattle (UW), a team of researchers found that improving the flow of proteins in and out of neurons has the potential to treat and perhaps even prevent Alzheimer’s. 

Alzheimer’s is a form of dementia affecting more than five million Americans. Alzheimer’s is often affected by genetics, but the greatest risk factor is aging. The disorder results in loss of memory, learning ability, reasoning and navigating skills, sense of identity, and even the ability to recognize one’s closest family members. 

Alzheimer’s is predominantly caused by the death of brain cells, which scientists believe is the accumulation of two types of proteins in the brain: amyloid beta, which collects in the space outside of brain cells, and phosphorylated tau, which builds up inside the neurons. 

Recently, researchers have proposed that this accumulation of proteins happens due to a malfunctioning protein trafficking system. 

The membrane-bound compartments that are largely responsible for transporting proteins from one place to another in the cell or shipping proteins into or out of the cell are called endosomes. A defect in the endosomal networks can prove critically detrimental as time progresses.

The research team at UW, led by Assistant Professor Jessica Young from the department of pathology, hypothesized that increasing protein trafficking in neurons in vitro can significantly decrease the accumulation of amyloid beta and a precursor of phosphorylated tau. 

To shed light on their inquiry, they obtained skin cells from consenting patients with Alzheimer’s and from healthy people with no dementia. They subjected these skin cells to conditions that caused them to reverse their development and become pluripotent stem cells. 

Pluripotent stem cells usually represent the earliest form of cells in development. They are able to differentiate into practically any cell depending on environmental stimuli. 

These induced pluripotent stem cells (iPSCs) can be treated to differentiate into neurons, and then the scientist can study these neurons in vitro. Induced pluripotent stem cells are exceptionally important in biomedical research because they allow scientists to study a patient’s own cells without having to experiment directly on the patient.

Since all cells in an individual share the same genome, these differentiated iPSCs induced from skin cells would share the same mutations as the neurons of an Alzheimer’s patient.  

These neurons differentiated from iPSCs were then treated with a compound that was found in animal studies to increase the activity of a protein complex involved in protein trafficking. 

The complex, called the retromer, directs how endosomal protein packages are transported in the network and end up at the correct destination. 

The compound, R33, did indeed boost the function of the retromer and led to a significant decrease in the accumulation of both amyloid beta and phosphorylated tau. 

The research team also used CRISPR, a gene editing tool, to determine that R33 could effectively lower phosphorylated tau even in cells that did not have accumulated amyloid beta, debunking the previous belief that an increase in amyloid beta causes an increase in phosphorylated tau.

“The findings suggest that something upstream is affecting the production of amyloid beta and phosphorylated tau independently,” Young said, according to ScienceDaily. “So one thing we’re going to work on going forward will be using these cell lines to identify what this upstream defect might be and whether it, too, could be a target for new therapeutics to treat Alzheimer’s.”

Although the two proteins seem to be closely linked, the result suggests that the pathway for phosphorylated tau accumulation is independent from that of amyloid beta.

Alzheimer’s is not only debilitating for the patient, slowly taking away all forms of independence and human dignity, but it is also devastating for the patients’ loved ones. One third of all seniors die with Alzheimer’s or another form of dementia.

Alzheimer’s currently has no cure or methods of prevention. The United States spent $259 billion on medical care for Alzheimer’s patients just last year. However, the number of diagnoses continue to rise.

Young’s next step is to identify what the upstream defects affecting the production of amyloid beta and phosphorylated tau independently are. 

She hopes that soon they can target these defects as potential new treatments for Alzheimer’s.

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