Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations [bulk RNA-Seq]

Frontotemporal dementia (FTD) due to MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. Mutant organoids show early upregulation of MAPT expresssion and glutamatergic signaling pathways, as well as regulators including the RNA-binding protein ELAVL4. By 6 months, tau-V337M organoids show specific loss of glutamatergic neuronsof layers affected in patients. Mutant neurons are susceptible to glutamate toxicity, which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. Overall design: We performed bulk RNA-sequencing on three isogenic pairs of cerebral organoids at 2, 4 and 6 months of differentiation, derived from patient iPSC lines carrying the MAPT V337M mutation, and CRISPR-corrected controls Samples 'S_72a01_4mo_b3_4' and 'S_6a02_4mo_b3_3' were outliers in 3D PCA, thereby removed in the downstream analyses