Despite the recognized association between Alzheimer’s disease (AD) and sleep disruptions, the mechanisms by which amyloid plaques and tau tangles interact or interfere with the brain’s sleep pathways remain undefined. Dr. Macauley has studied these mechanisms across several models to construct and understand the timeline of sleep changes relative to different AD pathologies. Her work has demonstrated that sleep disruption precedes significant accumulation of either amyloid or tau and is accompanied by overactive nerve cell signaling (hyperexcitability) and a breakdown (desynchronization) in how key brain networks communicate with each other. Follow-up work further demonstrated that this breakdown seems to be driven by changes in how the brain produces and uses energy. Here, Dr. Macauley will continue this line of work to establish whether the energy shifts she observed cause the sleep disruptions associated with AD pathologies.
The project consists of three experimental aims. In the first, her team will test their hypothesis that in response to early amyloid pathology, microglia produce excess lactate, which drives neuronal hyperexcitability and sleep disruptions. Lactate is a natural byproduct of energy production when oxygen is limited. Though best known for its buildup in muscles during intense exercise, its effects also impact other organs and cells. Previous work showed increased lactate production in amyloid mouse models, particularly around plaques, and that removing microglia altogether improved sleep in these mice. Dr. Macauley’s team has developed a mouse model in which a key gene required for lactate production has been removed from microglia. This model will be crossed with an amyloid mouse model to test whether lactate produced by microglia in response to amyloid pathology disrupts sleep. This ambitious aim will validate previous findings and provide a target for potential therapeutic intervention. The second aim will mirror the first aim, but in tau models. This will determine whether the early stages of tau pathology lead to similar energy and sleep changes as seen with amyloid pathology. If this is the case, targeting microglial lactate production therapeutically becomes even more enticing, as it would be effective against both hallmark AD pathologies. The final aim will then test whether stiripentol, an FDA-approved inhibitor of lactate production, can restore neuronal activity and sleep patterns in both amyloid and tau mice. This aim is crucial for demonstrating that inhibiting lactate production is just as effective as the genetic approaches utilized in the first two aims.
Overall, this ambitious proposal seeks to define microglial lactate production as a critical mechanism driving sleep disruptions in AD and to begin testing its inhibition as a therapeutic approach.
