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.

The strongest genetic risk factor for late-onset Alzheimer’s disease (AD) is Apolipoprotein E e4 (APOE4). With the goal of explaining how APOE4 influences risk of AD, we will suppress an APOE4 risk signal and understand the mechanism of cellular reprogramming to prevent AD in our “brain-in-a-dish” model. We hope this approach can identify new drug targets of APOE4 and open doors to novel therapeutic modalities.

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.