SorCS2 is a mammalian sorting receptor that is induced in astrocytes after stroke to support tissue regeneration (Malik et al., Glia 2020). It has been shown that SNP variants of SORCS2 have epistatic effects on Alzheimer’s disease (AD) risk (Reitz et al., Translational Psychiatry 2013), and that SorCS2 deletion in the AD mouse model causes decline in astrocyte number accompanied by a profound increase in toxic amyloid beta (Ab) levels (Network Glia Conference 2023, #341). These observations suggest that astrocyte-expressed SorCS2 may play a protective role not only after stroke, but also in AD. Thus, in this study we searched for SorCS2-dependent mechanisms implicated in astrocytic response to Ab. We tested the impact of stimulation with Ab-containing medium on wild-type and SorCS2 knock-out (SorCS2-KO) astrocytes and we analysed astrocyte viability, as well as the levels of apoptosis and stress-related markers, phospho-p38 kinase and cleaved CASP-3. Ab stimulation lead to reduced cell viability and enhanced stress, which tended to be more pronounced in SorCS2-KO astrocytes. We further propose that this SorCS2-dependent phenotype may be due to increased levels of p75 NTR receptor seen upon SorCS2 loss. Together our results confirm the vulnerability of astrocytes to Ab burden and highlight the importance of protective SorCS2 functions in the condition of Ab load seen in AD, which in part could be dependent on p75 NTR transduced signals. This study was supported by the NCN, Poland (2020/37/B/NZ3/00761) and the IDUB Program at UW, Poland.