Reprogramming Microglia through Astrocyte Manipulation in Alzheimer’s Brain
APOE4 risk signal called “matrisome” using “brain-in-a-dish” model generated from human induced pluripotent stem cells.
In Aim 1, we will reprogram microglia function by manipulating astrocyte matrisome signal. We will determine whether altering ligands in APOE 44 astrocytes modulate microglia function via CD33 and investigate how modulation of ligands in APOE 44 astrocytes affect CD33-D2 microglia. In Aim 2, we will investigate microglial response to the modulation of matrisome in amyloid plaque and tau deposition. We will examine microglia phagocytosis and Ab deposition with and without matrisome in “brain-in-a-dish” model systems and assess microglia-mediated tau accumulation and propagation.
We identified a human-specific, APOE4-dependent non-cell autonomous endophenotype, enhanced matrisome in astrocytes only when co-cultured with neurons. Enriched matrisome represent elevated phosphacan, a microglia CD33 ligand. This study will assess whether microglia can be targeted non-cell autonomously by modulating astrocyte-derived phosphacan in APOE4 carriers, which can reduce AD risk. Microglia are a difficult cell-type to target with genetic strategies as doing so initiates a pathogenic response to foreign DNA. A more plausible approach is genetic manipulation of astrocytes. The studies will provide proof of concept data for targeting astrocytes by genetic manipulation as a therapeutic strategy to modulate microglia function. This study will guide future drug screening efforts to identify compounds that can either target microglia directly or astrocytes to affect microglia as an alternative to genetic manipulation efforts.