Investigators will use molecular FRET imaging in a mouse model of dementia to gain a better understanding of inflammatory and toxic processes involved in Alzheimer’s disease.
Alzheimer’s disease is characterized by senile plaques that consist of amyloid beta peptide. The plaques are surrounded by immune microglial cells, which are the only immune cells that reside in the brain. Research has demonstrated that the amyloid beta peptide can induce microglial cells to produce inflammatory substances, including cytokines, chemokines and neurotoxic factors. These substances are thought to contribute to neurodegeneration that can lead to progressive cognitive and motor impairment. The processes by which this occurs, however, are not well understood.
The investigators found that immune microglial cells contain a receptor complex (called NALP3 inflammasome). NALP3 evolved to recognize aggregated proteins and the peptides that compose them. Its activation leads to generation of inflammatory cytokines, such as interleukin-1, and neurotoxic factors. They have found that cells from genetically modified mice that lack components of this NALP3 receptor complex fail to recognize these protein aggregates and do not mount an inflammatory response.
The investigators will use cellular FRET imaging, which shows how molecules affect one another, in mice that lack components of the NALP3 receptor complex. They will determine whether the mice are protected from developing dementia, and from damaging inflammation. They also will characterize the components that the modified NALP3 receptor lacks, for further development into potential therapeutic agents.