Obesity increases the risk for Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. For years, researchers assumed this connection was indirect—that obesity damaged the heart and blood vessels, which in turn reduced blood flow to the brain and increased dementia risk. However, recent studies are revealing that the relationship may be more direct than previously thought. For example, research by Dr. Wong has shown that fat cells in the body can send chemical signals to neurons and that these signals become harmful with obesity.
Adipocytes, or fat cells, release small bubble-like particles called extracellular vesicles (EVs)—like “messages in a bottle”—that travel to the brain where they interact with brain cells. In obesity, the content (or messages) of these EVs can change, altering their effects on the brain. Dr. Wong found that levels of the lipid phosphatidylethanolamine (PE) are elevated in EVs in obesity. When these PE-laden EVs reach the brain, they can generate large amounts of neuroinflammation, damage cells, and interfere with neuronal function. Dr. Wong hypothesizes that PE overload can drive AD progression and that using drugs to reduce PE levels can mitigate AD pathology. Here, he aims to study how these fat-derived EVs speed up Alzheimer’s changes in the brain and to test drugs that can restore a healthier lipid balance.
This project has two experimental aims. In the first, the Wong lab will investigate how PE contributes to AD progression. Experiments will be done in an amyloid mouse model and in mice expressing human APOE4. APOE4 is the strongest genetic risk factor for late-onset AD and has significant roles in handling and trafficking lipids throughout the brain and body. By investigating how APOE4 responds to elevated PE (lipid) levels, the Wong lab can determine if individuals with APOE4 are more vulnerable to the effects of PE. As part of this aim, they will also test whether ebselen, a small-molecule compound they identified as part of a drug screen, can counteract PE and protect against AD progression. The second aim will focus on understanding the cell-type-specific effects of PE and the cascade of changes that result from those effects. Their preliminary data suggest that PE drives interactions among neurons, microglia, and T cells. They plan to fully characterize these interactions and then validate their findings in postmortem human brain tissue.
This project explores a potential driver of AD that has been relatively understudied until recently. In doing so, Dr. Wong’s team aims to identify a novel target for therapeutic intervention. This project also helps us understand how obesity, a common and potent risk factor for AD, contributes to AD progression and can help guide individual treatment plans in the future.
