Dr. Glass is exploring in detail the timing and mechanisms by which immune cells in the brain respond to a peripheral immune response produced by an injection of the neuroinflammatory agent LPS. The Glass lab’s focus is on the role of a protein made by macrophages and microglia called TLR4. LPS binds to TLR4 and triggers a cascade of signals that prompts cells to increase the production of inflammatory cytokines while decreasing anti-inflammatory ones. Other molecules and toxins (not just LPS) also activate TLR4, and there is experimental and genetic evidence that TLR4 is involved in Alzheimer’s disease, with both beneficial and detrimental effects reported. The team hypothesizes that LPS activates microglia and triggers inflammation in the brain through TLR4, either by direct interactions or through indirect mechanisms.
The Glass project has three aims to map the brain’s response to peripheral inflammation. In the first aim, they are focusing on determining the time course of microglia activation after peripheral LPS injection in an amyloid mouse model. In the second aim, the team is investigating whether microglia or peripheral macrophages, including border associated macrophages (BAMs) must express TLR4 for LPS to activate microglia and inflammation. In the third aim, the team is exploring whether targeting peripheral immune responses can prevent or block the effect seen in the brain. This last aim has clear therapeutic relevance as targeting peripheral inflammation to treat Alzheimer’s disease is more practical and appealing than delivering a drug into the brain.
The lab has made steady progress validating their hypothesis. For their first aim, they observed that microglia rapidly alter their gene activity within just an hour of LPS exposure—an unexpectedly fast response. Time-course studies to further characterize this response are still underway. This work is being complemented with spatial transcriptomics to map these changes in detail. Delays in acquiring the necessary mice slowed progress on aim two, but breeding pairs are now available, and experiments are moving forward. For Aim 3, the team discovered that removing peripheral immune cells had only a modest effect on microglial responses to LPS but triggered a type I interferon response. This finding suggests that complex signaling is happening between immune cells and microglia.
