mouse models

What’s Fat Got to do With Alzheimer’s?

/ Karen Ring / Leave a comment
good_and_bad_eggs_xl

(Image credit: FineCooking.com)

Diets these days are a dime a dozen, and dietary trends come and go. First eggs were “out” because they contain cholesterol, but now they are back “in” because we now know that some types of cholesterol can be actually good for the body. Then there was the era of “fat-free” or “reduced-fat” foods. This was all the rage in the 90s until scientists realized that eliminating healthy fats from your diet can have negative consequences on your health.

The theories behind different diets evolve constantly much like the theories behind complicated neurodegenerative diseases like Alzheimer’s disease (AD). Alzheimer’s is a debilitating disease that slowly robs patients of their minds, leaving them as shadows of their former selves. AD affects 47.5 million people globally with 7.7 million new patients diagnosed every year, thus making the disease one of the most important unmet medical needs to be addressed.

The causes of AD have eluded scientists for over a century. However, the main theory behind what causes AD involves the buildup of toxic proteins in the brain. These proteins accumulate to form structures called plaques and tangles that impair brain function and kill off brain cells.

Unfortunately, there is no cure for AD or treatments to stop its progression. This sobering fact is not due to a lack of effort by scientists and pharmaceutical companies. Dozens of drug therapies have or are being tested in clinical trials, many of them focusing on the removal of toxic protein levels in people with the disease. While there have been some pretty dramatic failures in these trials, a few are starting to show encouraging results.

Link Between Abnormal Fat Metabolism and Alzheimer’s Disease

Now, a new theory on AD involving the build up of toxic fat molecules in the brains of AD patients has been thrown into the mix. In a study published Thursday in Cell Stem Cell, scientists from Montreal reported the presence of fat droplets in AD patient brains in areas surrounding brain stem cells. Brain stem cells are responsible for growing new brain cells (such as nerves) and maintaining overall brain function and health. The scientists discovered that the fat droplets actually prevented the regenerative abilities of the brain stem cells, leading them to believe that the accumulation of fat droplets in the brain could be a cause of AD.

Fat is used as an energy source by cells and organs in the body in a process called “fatty acid metabolism”. Fat metabolism is very important for proper brain development but also in maintaining brain health and function in adults. Problems with fat metabolism in humans can cause diseases such as obesity, diabetes, and heart disease. So one can imagine that problems with fat metabolism in the brain could also have serious consequences.

In this study, scientists used a genetic mouse model of AD that had a “triple-threat” of genetic mutations that cause AD in humans. They studied the brain stem cells in these mice and found that the support cells surrounding the stem cells were full of fat droplets. They also noticed that when the fat droplets were present, the brain stem cells were not dividing to generate new brain cells (which is a common defect associated with AD). When they looked at brain tissue from nine AD patients, they also observed a similar pattern of an increased concentration of fat droplets surrounding areas of brain stem cells compared to healthy human brain tissue.

fat droplets

AD patient brains (lower panel) have more fat droplets shown in red than normal healthy brains (upper panel). (Hamilton et al., 2015)

Using a fancy science technique called mass spectrometry, the scientists found that the fat droplets were made up of a fat triglyceride called oleic acid, which is a common component of vegetable and animal fats. To prove that oleic acid was bad for brain stem cells, they took normal healthy mice and injected oleic acid into their brains. They observed that adding this fat negatively affected the stem cells’ regenerative ability to divide. Going one step further, the scientists used drugs to block the formation of oleic acid in their AD mouse model, and saw that removing this fat allowed the brain stem cells to divide and function properly.

The major conclusions generated from this study were summarized nicely by senior author Karl Fernandes in a news release:

We discovered that these fatty acids are produced by the brain, that they build up slowly with normal aging, but that the process is accelerated significantly in the presence of genes that predispose to Alzheimer’s disease. In mice predisposed to the disease, we showed that these fatty acids accumulate very early on, at two months of age, which corresponds to the early twenties in humans. Therefore, we think that the build-up of fatty acids is not a consequence but rather a cause or accelerator of the disease.

 

Don’t Count Your Chickens Just Yet

While this study suggests that fat accumulation in the brain is a cause of AD, more research will need to be done to confirm that abnormal fat metabolism is the culprit. Some experiments can be done quickly such as treating their AD mouse model with the drugs that block the formation of the “bad fat” and monitoring them for an extended time period to see if blocking oleic acid accumulation prevents the onset of AD symptoms like memory loss. Other experiments, such as therapeutically targeting abnormal brain fat deposits in human, will be more long term projects with unknown results.

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Dr. Alois Alzheimer

Nontheless, this study nicely ties back to an observation by Dr. Alois Alzheimer who first reported about AD in 1906 . When he dissected the brains of AD patients who had passed away, he found five major pathologies that distinguished their brains from healthy brains. One of these traits was an increased concentration of fat droplets. Thus findings from Fernandes and his group revive a century old notion that fat metabolism could be a cause of AD and open doors for the development of new therapeutic strategies to fight AD.

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New Regenerative Liver Cells Identified

/ Karen Ring / Leave a comment

It’s common knowledge that your liver is a champion when it comes to regeneration. It’s actually one of the few internal organs in the human body that can robustly regenerate itself after injury. Other organs such as the heart and lungs do not have the same regenerative response and instead generate scar tissue to protect the injured area. Liver regeneration is very important to human health as the liver conducts many fundamental processes such as making proteins, breaking down toxic substances, and making new chemicals required to digest your food.

The human liver.

The human liver

Over the years, scientists have suggested multiple theories for why the liver has this amazing regenerative capacity. What’s known for sure is that mature hepatocytes (the main cell type in the liver) will respond to injury by dividing and proliferating to make more hepatocytes. In this way, the liver can regrow up to 70% of itself within a matter of a few weeks. Pretty amazing right?

So what is the source of these regenerative hepatocytes? It was originally thought that adult liver stem cells (called oval cells) were the source, but this theory has been disproved in the past few years. The answer to this million-dollar question, however, likely comes from a study published last week in the journal Cell.

Hybrid hepatocytes (shown in green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

Hybrid hepatocytes (green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

A group at UCSD led by Dr. Michael Karin reported a new population of liver cells called “hybrid hepatocytes”. These cells were discovered in an area of the healthy liver called the portal triad. Using mouse models, the CIRM-funded group found that hybrid hepatocytes respond to chemical-induced injury by massively dividing to replace damaged or lost liver tissue. When they took a closer look at these newly-identified cells, they found that hybrid hepatocytes were very similar to normal hepatocytes but differed slightly with respect to the types of liver genes that they expressed.

A common concern associated with regenerative tissue and cells is the development of cancer. Actively dividing cells in the liver can acquire genetic mutations that can cause hepatocellular carcinoma, a common form of liver cancer.

What makes this group’s discovery so exciting is that they found evidence that hybrid hepatocytes do not cause cancer in mice. They showed this by transplanting a population of hybrid hepatocytes into multiple mouse models of liver cancer. When they dissected the liver tumors from these mice, none of the transplanted hybrid cells were present. They concluded that hybrid hepatocytes are robust and efficient at regenerating the liver in response to injury, and that they are a safe and non-cancer causing source of regenerating liver cells.

Currently, liver transplantation is the only therapy for end-stage liver diseases (often caused by cirrhosis or hepatitis) and aggressive forms of liver cancer. Patients receiving liver transplants from donors have a good chance of survival, however donated livers are in short supply, and patients who actually get liver transplants have to take immunosuppressant drugs for the rest of their lives. Stem cell-derived liver tissue, either from embryonic or induced pluripotent stem cells (iPSC), has been proposed as an alternative source of transplantable liver tissue. However, safety of iPSC-derived tissue for clinical applications is still being addressed due to the potential risk of tumor formation caused by iPSCs that haven’t fully matured.

This study gives hope to the future of cell-based therapies for liver disease and avoids the current hurdles associated with iPSC-based therapy. In a press release from UCSD, Dr. Karin succinctly summarized the implications of their findings.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation.”

This exciting and potentially game-changing research was supported by CIRM funding. The first author, Dr. Joan Font-Burgada, was a CIRM postdoctoral scholar from 2012-2014. He reached out to CIRM regarding his publication and provided the following feedback:

CIRM Postdoctoral Fellow Jean Font-Burgada

CIRM postdoctoral scholar Joan Font-Burgada

“I’m excited to let you know that work CIRM funded through the training program will be published in Cell. I would like to express my most sincere gratitude for the opportunity I was given. I am convinced that without CIRM support, I could not have finished my project. Not only the training was excellent but the resources I was offered allowed me to work with enough independence to explore new avenues in my project that finally ended up in this publication.”

 

We at CIRM are always thrilled and proud to hear about these success stories. More importantly, we value feedback from our grantees on how our funding and training has supported their science and helped them achieve their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies such as this one are an encouraging sign that we are making progress towards to achieving this goal.

Related links:

UCSD Press Release

CIRM Spotlight on Liver Disease Research

CIRM Spotlight on Living with Liver Disease

Stay on Target: Scientists Create Chemical ‘Homing Devices’ that Guide Stem Cells to Final Destination

/ cirmweb / 1 Comment

When injecting stem cells into a patient, how do the cells know where to go? How do they know to travel to a specific damage site, without getting distracted along the way?

Scientists are now discovering that, in some cases they do but in many cases, they don’t. So engineers have found a way to give stem cells a little help.

As reported in today’s Cell Reports, engineers at Brigham and Women’s Hospital (BWH) in Boston, along with scientists at the pharmaceutical company Sanofi, have identified a suite of chemical compounds that can help the stem cells find their way.

Researchers identified a small molecule that can be used to program stem cells (blue and green) to home in on sites of damage. [Credit: Oren Levy, Brigham and Women's Hospital]

Researchers identified a small molecule that can be used to program stem cells (blue and green) to home in on sites of damage. [Credit: Oren Levy, Brigham and Women’s Hospital]

“There are all kinds of techniques and tools that can be used to manipulate cells outside the body and get them into almost anything we want, but once we transplant cells we lose complete control over them,” said Jeff Karp, the paper’s co-senior author, in a news release, highlighting just how difficult it is to make sure the stem cells reach their destination.

So, Karp and his team—in collaboration with Sanofi—began to screen thousands of chemical compounds, known as small molecules, that they could physically attach to the stem cells prior to injection and that could guide the cells to the appropriate site of damage. Not unlike a molecular ‘GPS.’

Starting with more than 9,000 compounds, the Sanofi team narrowed down the candidates to just six. They then used a microfluidic device—a microscope slide with tiny glass channels designed to mimic human blood vessels. Stem cells pretreated with the compound Ro-31-8425 (one of the most promising of the six) stuck to the sides. An indication, says the team, Ro-31-8425 might help stem cells home in on their target.

But how would these pre-treated cells fare in animal models? To find out, Karp enlisted the help of Charles Lin, an expert in optical imaging at Massachusetts General Hospital. First, the team injected the pre-treated cells into mouse models each containing an inflamed ear. Then, using Lin’s optical imaging techniques, they tracked the cells’ journey. Much to their excitement, the cells went immediately to the site of inflammation—and then they began to repair the damage.

According to Oren Levy, the study’s co-first author, these results are especially encouraging because they point to how doctors may someday soon deliver much-needed stem cell therapies to patients:

“There’s a great need to develop strategies that improve the clinical impact of cell-based therapies. If you can create an engineering strategy that is safe, cost effective and simple to apply, that’s exactly what we need to achieve the promise of cell-based therapy.”