BACKGROUND: Mutations in microtubule-associated protein tau (MAPT) gene are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, e.g high levels of tau phosphorylation, are also present in early development. iPSC-neurons have gene expression signatures similar to fetal neurons, and iPSC-neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC-neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis, we investigated the levels of proteasome subunits in developing iPSC derived neurons and measured the proteasome activity of iPSC-neurons throughout development. To test whether manipulation of proteostasis in iPSC-neurons could lead to tau pathology we treated cells with a proteasome inhibitor, and measured changes in total and phosphorylated tau, proteasome subunits and autophagy regulators. METHODS: Human cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at during neuronal development (DIV 0, 10, 30 and 100) and after proteasome inhibition treatments. RESULTS: We show that proteasome activity decreases during the differentiation of iPSCs to cortical neurons, accompanied by a reduction in levels of the proteasome regulatory subunits Rpt6 and Rpn6. Proteasome inhibition in WT neurons does not lead to a significant change in total or phosphorylated tau levels but resulted in an increase in the autophagy associated protein BAG3, together with an induction of tau cleaved by caspase-3 at Asp421. CONCLUSION: Proteasome activity decreases during the differentiation of iPSCs into neurons, which may be due to a reduction in in proteasome regulators. Our results suggest that proteasome inhibition causes an increase in tau cleavage which may be preferentially cleared through the autophagy pathway. The ability of these 'fetal-like' neurons to adapt and upregulate their protein clearance system may be enhanced compared to FTD brain tissue. In ongoing work we are investigating proteasome expression and activity in FTD post-mortem tissue as well as the localisation and interactions of tau and the proteasome after proteasome inhibition treatments.