Dmm019489 1265..1278
نویسندگان
چکیده
Animal models of familial juvenile onset of Alzheimer’s disease (AD) often fail to produce diverse pathological features of the disease by modification of single gene mutations that are responsible for the disease. They can hence be poor models for testing and development of novel drugs. Here, we analyze in vitro-produced stem cells and their derivatives from a large mammalian model of the disease created by overexpression of a singlemutant humangene (APPsw).Weproduced hemizygous and homozygous radial glial-like cells following culture and differentiation of embryonic stem cells (ESCs) isolated from embryos obtained frommated hemizygous minipigs. These cells were confirmed to co-express varying neuralmarkers, includingNES,GFAP and BLBP, typical of type one radial glial cells (RGs) from the subgranular zone. These cells had altered expression of CCND1 and NOTCH1 and decreased expression of several ribosomal RNA genes. We found that these cellswere able to differentiate into astrocytes upon directed differentiation. Theastrocytesproducedhaddecreasedαand β-secretase activity, increased γ-secretase activity and altered splicing of tau. This indicates novel aspects of early onset mechanisms related to cell renewal and function in familial AD astrocytes. These outcomes also highlight that radial glia could be a potentially useful population of cells for drug discovery, and that altered APP expression and altered tau phosphorylation can bedetected in an in vitromodel of the disease. Finally, it might be possible to use large mammal models to model familial AD by insertion of only a single mutation.
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