Femke Feringa (FGA) received a ZonMW VENI grant to develop her independent research line on how the Alzheimer risk mutation APOE4 contributes to senescence (cell aging) in human astrocytes generated from induced pluripotent stem cells.
CONTRIBUTE TO EXIT, senescence as a risk for AD development
Due to our aging society the number of patients that suffer from Alzheimer’s Disease (AD) is expected to double in the next two decades. Fundamental understanding of the origin of this disease is still lacking and hence no curative treatment is currently available.
Senescence is one of the main hallmarks of aging, characterized by irreversible cell cycle exit and a pro-inflammatory secretory phenotype. The term senescence was originally defined in the field of oncology, yet an increase in senescent cells has also been described in the AD brain. Importantly, removal of senescent cells in AD mouse models alleviated AD pathology suggesting a role in disease development. The major AD risk gene APOE alters lipid and immune metabolism in glia, yet it is unknown how this mutation contributes to AD development. Femke’s preliminary results ssuggest that the disease-associated APOE allele E4 contributes to senescence induction in astrocytes.
Femke will use human iPSC-derived astrocytes and postmortem brain tissue to establish if APOE4 expression impacts the senescent cell fate in astrocytes, and develop a high-throughput flow-cytometry based drug screen to investigate which underlying targets or pathways drive the effect of ApoE4 on senescence in astrocytes. The mechanistic insights gained from this study can lead to novel and more specific therapeutical strategies targeting senescent cells to revert AD pathology.