Genetic risk is only part of the equation for sporadic forms of Alzheimer’s disease (AD). Other risk factors include lifestyle-related issues like poor cardiovascular health and midlife obesity. These risk factors share a common consequence: they involve disruptions in how the body processes fats, also known as lipid metabolism. Lipids (fats) are essential for many of the body’s basic functions, including providing structure to cell membranes and ensuring proper cellular trafficking. However, lipid overload may drive cells into a proinflammatory state that becomes harmful if not resolved. The complex biology of cells such as neurons and microglia makes them particularly susceptible to changes in both lipid metabolism and protein trafficking. Drs. Stevens and Greka (and their teams) aim to understand the interplay between lipids and protein trafficking, with the ultimate goal of gaining novel insights into specific signaling pathways that could be targeted for future drug development.
In their previously funded CureAlz project, the Greka and Stevens labs discovered that certain fats found in the blood—specifically saturated free fatty acids (FFAs)—could harm microglia. These fats either killed microglia or pushed them into states that worsened Alzheimer’s pathologies when tested in mice. The labs found that a protein called CD36, which shuttles lipids into microglia, might play a role in this toxic effect. Since microglia and neurons are intertwined in the brain, the Greka and Stevens labs are interested in exploring the effects of FFAs on the interaction between these cell types. They hypothesize that exposure to toxic lipids negatively impacts the interrelated functionality of microglia and neurons and hope to identify the molecules that mediate these effects.
At the close of the first year of funding, the Greka and Stevens labs have made substantial progress, working on both microglial and neuronal systems. To further understand how microglia respond to lipids, they are studying mice that lack the lipid receptor CD36 after exposure to three separate challenges: lipopolysaccharide (LPS) exposure, demyelination, and a high-fat diet. After each challenge, they are measuring microglial activation states and evaluating functional changes, including alterations in the endolysosomal pathway that may affect protein trafficking to the cell membrane. They are also conducting these experiments in CD36 knockout mice crossed with an amyloid mouse model to investigate how amyloid pathology modifies the microglial response to lipid challenges.
Additionally, the teams are exploring the role of TMEDs, a family of cargo receptors expressed in neurons, which appears to be critical for lipid exchange and the proper transport of proteins, such as APP, to the cell membrane. Once APP is at the cell membrane, enzymes can cut it in a specific sequence to release beta amyloid peptides into the space among neurons. They are using biochemical assays, imaging, multi-omics, as well as behavioral assays to assess the role of TMEDs in APP trafficking. In addition, they are assessing the impact of a small molecule, which targets TMEDs, in both in vitro systems and in amyloid mouse models. They predict that disrupting TMED activity may restore APP processing and potentially reverse amyloid-related pathologies in mice.
