The choroid plexus epithelium (CPE) is a highly secretory single cell layer, responsible for the production of cerebrospinal fluid (CSF) and the clearance of toxic agents. Additionally, the CPE forms an anatomical barrier that prevents paracellular leakage from the blood into the CSF and is called the blood-CSF barrier (BCSFB). Healthy aging severely affects CPE morphology and we recently discovered that also barrier function is affected. During Alzheimer’s disease (AD), more severe morphological changes are observed at the CPE and this is correlated with even more pronounced impairment of secretion, synthesis, and transport at the CPE cell layer. These impairments favor the decrease of CSF turnover and diminish the levels of CP-derived proteins involved in Aß sequestration, favoring Aß oligomerization. We recently studied the toxic effects of Aß on the CPE in vivo by icv injection of Aß. Interestingly, this revealed that Aß injection increases BCSFB permeability and has strong effects on CPE gene expression. This suggests that the CPE plays a role in AD pathogenesis. Consequently, unraveling the CPE processes that are disturbed during AD could potentially lead to the identification of new therapeutics. Here, we will establish an in vitro model system, we will perform high throughput screening to identify compounds that prevent Aß-induced permeability and we will search for other relevant read-outs of Aß-induced toxicity that are potentially important in AD pathology.