Alzheimer’s disease (AD) has a remarkably complex, multifactorial pathogenesis, which makes it difficult to diagnose and treat. The disease affects multiple biological systems and, because so many systems are involved, researchers have struggled to develop a single treatment that can halt the disease’s progression. However, this complexity also presents an opportunity: if multiple systems are involved, researchers can target the disease through several pathways simultaneously. For example, some researchers believe that combining drugs that reduce harmful protein buildup in the brain, such as the FDA-approved amyloid antibody treatments Leqembi and Kisunla, with drugs that also reduce brain inflammation could be more effective than approaches that focus solely on one aspect of the disease. This proposal explores a combination strategy by testing drugs that address two problems in the Alzheimer’s brain: inflammation and impaired energy production.
The role of neuroinflammation in AD is well-established and widely studied. In comparison, the energy changes in the brain linked to AD have received less attention. In AD, the brain’s ability to process glucose, the main sugar our bodies use for energy, is decreased. This decline leads to energy shortages in cells and is associated with impaired neuron activity. The Ghosh and Schlachetzki labs, in collaboration with others, discovered that fructose 2,6-biphosphate (F2,6BP), which helps cells use glucose for energy, is decreased in Alzheimer’s. Without it, the brain’s energy production drops. When faced with an energy deficit, cells utilize other metabolic pathways to generate the energy they need. However, some of these pathways have drawbacks, as they create byproducts that damage DNA, proteins, and the connections between brain cells. This damage triggers immune cells to cause inflammation, which worsens the energy problem. A vicious cycle is created: low energy production causes cellular damage, damage leads to inflammation, and inflammation makes the energy problem worse. Drs. Ghosh and Schlachetzki are experts in the mechanisms underlying this damaging cycle. They hypothesize that the cycle can be broken through a treatment that combines F2,6BP to boost energy production with a powerful anti-inflammatory molecule called IKK2i, developed by the Ghosh group, which blocks a key inflammation pathway.
In this project, the Ghosh and Schlachetzki labs will evaluate whether their combination treatment, targeting both energy and inflammation, can restore energy balance, reduce inflammation, restore neuronal function, and prevent the cell damage and death that drive AD. They have three experimental aims. First, they will identify where F2,6BP binds within the mitochondria, the cellular structure responsible for energy production and glucose metabolism. This step is crucial to validate the mechanism behind their approach. Second, they will focus on testing the combined effects of F2,6BP and IKK2i in cultured microglia and neurons derived from AD patients. Specifically, they will verify whether these treatments, either alone or in combination, reduce inflammation-triggering debris from mitochondria. Finally, they will test the combined therapy in an amyloid mouse model. They plan to measure several key outcomes, including changes in amyloid pathology, cell-specific inflammation markers, and indicators of mitochondrial function. This aim will also be essential for determining the optimal dose for each drug when used together, a key step toward translating this approach into potential clinical applications.
This project tests a promising co-therapy approach targeting two vital and interconnected hallmarks of AD: inflammation and energy deficiencies. This work has the potential to provide not only a translatable therapeutic approach but also a deeper understanding of the interactions between cellular metabolism and neuroinflammation.
