Summary
This project aims to investigate the distinct roles of peripheral myeloid immunity versus brain microglia in the cognitive decline associated with aging and Alzheimer's disease, using preclinical murine models and human myeloid cells.
The role of peripheral versus brain myeloid immunity in the cognitive decline of aging and Alzheimer's disease
US · IL
NIH
grant
awarded
#nih-4R01AG079131-02
What they want
The research will use novel bone marrow transplantation and genetic strategies to compare the relative contributions of the peripheral myeloid system and brain microglia to age- and AD-associated cognitive decline. It will test whether age-associated changes in the peripheral myeloid system alone are sufficient to promote cognitive decline, and conversely, whether microglial dysfunction alone can cause cognitive decline, independent of the peripheral myeloid system. The TREM1 pathway will be used to parse out relative contributions and define immune-metabolic mechanisms in murine models (Aims 1 and 2). Aim 3 will determine the function of TREM1-mediated immune responses in human myeloid cells.
Deliverables
- Understanding of the relative contributions of brain microglial vs peripheral myeloid compartments to age- and AD-associated cognitive decline
- Definition of immune-metabolic mechanisms of action underlying these contributions in murine models
- Determination of the function of TREM1-mediated immune responses in human myeloid cells
- Information to inform development of effective, disease-modifying therapies
Technical requirements
- Novel bone marrow transplantation approach
- Complementary genetic strategy targeting microglia
- Use of preclinical murine models of aging and AD
- Investigation of the TREM1 (Triggering Receptor Expressed on Myeloid cells-1) pathway
- Analysis of human myeloid cells
