Obesity accelerates Alzheimer’s-linked plaque buildup in the brain

Obesity has been linked to diseases like diabetes, heart disease, and hypertension for a long time. Excess weight is now linked directly to Alzheimer's in a new study — with tiny messengers going back and forth between fat tissue and the brain. The finding may explain why obesity raises the risk of Alzheimer's and create new ways to prevent it.

Houston Methodist researchers led the study. They focused their study on extracellular vesicles, tiny bubble-like particles excreted by cells to talk to the rest of the body. These vesicles are loaded with cargo like fat particles called lipids, and they have the capability of crossing even the blood-brain barrier.

The scientists wondered: do vesicles in fat people have different lipids than those in thin people? And if so, might these differences make a difference in the buildup of amyloid-β plaques, clumps of gluey protein that mark Alzheimer's disease?

To find out the questions mentioned above, researchers collected fat tissue samples from subjects. They separated extracellular vesicles from such samples and analyzed their molecular content. Researchers compared vesicles in lean and obese individuals, and subsequently they evaluated the impact of such vesicles on amyloid aggregation in cell cultures and mouse models.

The experiments showed dramatic contrasts. Obese individuals' vesicles carried lipid cargo that caused amyloid proteins to clump up faster and much more significantly than vesicles from normal-weight volunteers. In other words, fat tissue in obesity can send signals that speed one of the first and most damaging processes in Alzheimer's disease.

The study found that all lipids are not created equal. Certain fat molecules were more common in obese people's vesicles, and those lipids seemed to hasten the clumpy deposition of amyloid-β.

"Obesity is now the most prevalent modifiable risk factor for dementia in the US," according to Stephen Wong, Ph.D., senior author of the study and director of the T. T. & W. F. Chao Center for BRAIN at Houston Methodist. "Our findings provide a potential biological explanation for this correlation."

In showing that body fat vesicles can cross into the brain and deliver this toxic payload, the researchers revealed a possible connection between two of the country's largest health concerns.

Obesity afflicts nearly 40 percent of Americans. More than seven million Americans live with Alzheimer's disease, which is expected to be on the rise as the population ages. Understanding how the two diseases are perhaps connected gives researchers a new target on which to intervene.

If researchers can hinder or alter the vesicle messages out of fat tissue, one may be able to slow down or even fend off Alzheimer's in those who are more susceptible. "Interfering with these tiny cell messengers and blocking their poisonous communication can reduce the risk of Alzheimer's disease in people with obesity," Wong said.

The study, involving colleagues at The Ohio State University's Wexner Medical Center and the University of Texas Health Science Center at San Antonio, suggests a new way of thinking about preventing Alzheimer's disease beyond the traditional suspects of genes and age.

One of the research strengths is that it is a multi-layered research using human subjects, lab experiments, and animal models. Having the results from the multiple test methods strengthens the findings compared to a single test method.

Nonetheless, the study has one constraint. Rapid amyloid buildup was observed in laboratory and animal studies, not in human brains in the world. Both Alzheimer's and obesity are complex conditions influenced by many pathways like genetics, integrity of blood vessels, and metabolism. This study gives a possible link, but much needs to be confirmed to make it so in humans.

Subsequent studies will examine whether the inhibition or alteration of the cargo of these vesicles can slow down amyloid buildup. Scientists also want to determine if there are biomarkers that indicate the presence of poisonous vesicle signals, which would enable earlier detection of those at risk.

The research group wants one day to have doctors use therapies to block these vesicles from delivering toxic fat molecules into the brain. These treatments would be used in conjunction with lifestyle treatments like diet and exercise to lower risk for Alzheimer's.

This study suggests that weight control may do more than improve heart and metabolic health — it can also protect the brain from Alzheimer's disease. Researchers could develop drugs that block poisonous signals from traveling from fat tissue into the brain by targeting extracellular vesicles.

Diagnostic tools, such as biomarkers in spinal fluid or blood, could also be a product of this work.

For individuals, the study emphasizes how weight management may reduce the risk of both bodily and intellectual decline, potentially altering the manner in which Alzheimer's prevention might be sought in the future.

Research findings are available online in the journal Alzheimer s & Dementia.

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