Alzheimer's disease (AD) is characterized by presenting a complex pathology, not fully resolved yet. This
fact, together with the lack of reliable models, has impeded the development of effective therapies.
Recently, several studies have shown that functional glial cell defects have a key role in the pathology of
AD. However, this glial dysfunction, currently, cannot be correctly modeled using the available animal
models, so we hypothesized that cells derived from Alzheimer's patients can serve as a better platform for
studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different
types of neural cells, which can be used for disease modeling, identification of new targets and drugs
development.
Methods:
We have a collection of hiPSCs derived from patients with sporadic forms of AD stratified based on APOE
genotype. We have differentiated these cells towards neural cells and mature them to neurons or
astrocytes using a serum-free approach, to assess intrinsic differences between those derived from AD
patients or healthy controls.
Results:
We have implemented a serum-free approach and generated neural precursors and astrocytes from all the
lines tested. We observe differences at the phenotypic level and a reduced capacity to differentiate
towards neural lineage in those lines derived from APOE4 carriers.
Conclusions:
Our preliminary data suggest intrinsic differences in the neural differentiation capacity between cell lines
derived from APOE4 or APOE3 carrier subjects. Further experiments would contribute to elucidate novel
pathogenic pathways associated with neurodegeneration and susceptible of therapeutic modulation, likely
contributing to the development of new effective drugs against AD.This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from
European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by Junta de Andalucia through
Consejería de Economía y Conocimiento grants UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG) and
US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014-2020, and Programa Operativo de
Empleo Juvenil SNGJ4-11 to LCP.
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