Houston Methodist study identifies fat molecule linking obesity to Alzheimer's progression

Scientists at Houston Methodist have identified a specific class of fat molecules that may help explain how obesity contributes to the progression of Alzheimer’s disease. The research shows that obesity elevates levels of phosphatidylethanolamines (PEs) in body tissues; these lipids are packaged into tiny particles that travel to the brain, where they interfere with cell communication, weaken immune defenses, and encourage the accumulation of amyloid proteins, a hallmark of the disease (Houston Methodist).

The study, co-led by Stephen Wong, Ph.D., the John S. Dunn Presidential Distinguished Chair in Biomedical Engineering, and Li Yang, Ph.D., a research associate in the Chao Center for BRAIN at Houston Methodist, was published in the journal Molecular Neurodegeneration (EurekAlert). PEs are lipids found in cell membranes throughout the body. According to the findings, obesity increases their abundance; the molecules are then loaded into particles capable of reaching the brain. Once there, they disrupt lipid homeostasis, impair microglial identity and signaling, affect neuron-microglia communication, contribute to T-cell functional exhaustion, and alter membrane organization in ways that increase amyloidogenic processing in excitatory neurons (Drug Discovery News).

“Obesity can change how signals travel to the brain,” Wong said in a statement. “The good news is that this may be something we can treat. Instead of looking at Alzheimer’s risk tied to obesity as just a metabolic problem, this research suggests we may be able to target the process that connects those changes to the brain” (ScienceDaily).

Using integrative lipidomics, single-nucleus RNA sequencing, proteomics, high-resolution imaging, extracellular vesicle models, and mouse models of Alzheimer’s disease, the team demonstrated these effects. They also found that restoring a healthier balance of PEs reduced lipid dysregulation. In Alzheimer’s disease models, correcting the imbalance improved brain function and cognitive performance, including learning and memory (Houston Methodist).

In further experiments, the researchers identified the compound ebselen, known for antioxidant activity, as capable of restoring PE lipid homeostasis through a previously unrecognized mechanism involving regulation of PE metabolism. Treatment of Alzheimer’s mouse models with ebselen restored PE balance in the brain, improved neuroimmune function, decreased lipid dysregulation, and boosted cognitive performance (Drug Discovery News).

Wong noted that while the mouse results were encouraging, it remains too early to determine whether ebselen or similar approaches could serve as preventive treatments in people with obesity. Additional studies are needed to translate PE-targeted interventions into human prevention or therapy strategies, according to Yang (EurekAlert).

The work builds on established epidemiological links showing that midlife obesity is associated with substantially elevated dementia risk. Collaborators included researchers from the University of Texas at San Antonio, Boston University, and Ohio State University. Funding came from the Cure Alzheimer’s Fund, the T.T. and W.F. Chao Foundation, and the John S. Dunn Research Foundation (ScienceDaily).

According to the Centers for Disease Control and Prevention, more than 6.5 million Americans are living with Alzheimer’s disease, a figure projected to approach 14 million by 2060. The researchers hope the identification of this PE-driven adipose–brain–neuroimmune axis will support earlier intervention strategies for people whose metabolic health places them at elevated risk (Houston Methodist).