Influence of cytokines on microglial metabolism during Alzheimer’s disease

• Applicant: Professor Alexander Mildner, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500297100

Microglia play a crucial role in maintaining brain health by eliminating dead cells and preserving equilibrium. Under normal circumstances, these cells rely on oxidative phosphorylation (OxPhos) for energy production, a slow but consistent process well-suited for their routine functions. However, in neurodegenerative conditions such as Alzheimer's disease (AD), where harmful substances like amyloid-beta plaques accumulate, microglia shift to glycolysis, a faster energy production method. While this allows for faster inflammatory responses, it also results in intracellular lipid accumulation, hampering their capacity to effectively degrade phagocytosed plaque-derived particles. Accordingly, recent studies have revealed that in AD, microglia can become overwhelmed by fat deposits, triggering inflammation and exacerbating the disease. Our research explores whether reverting microglia to OxPhos could improve their ability to process these lipid deposits more efficiently and decrease amyloid-beta plaque accumulation. A promising approach involves using cytokines, immune signaling molecules that have shown improvement in AD mouse models and are currently undergoing clinical trials. However, the underlying molecular mechanisms of this cytokine treatment remain unclear. We hypothesize that the beneficial effect may be due to altering microglia's energy utilization, returning them to OxPhos, which is more effective for fat breakdown. This research direction could lead to new therapies that enhance microglia's capacity to manage brain plaques, potentially slowing disease progression like Alzheimer's. This perspective may provide new insights into microglial adaptability and cytokine signaling, possibly leading to innovative treatments for neurodegenerative disorder

• DFG Programme: Priority Programmes
• Subproject of: SPP 2395: Local and Peripheral Drivers of Microglial Diversity and Function
• International Connection: Finland