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

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(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.

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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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