Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutation.
Bowles, K. R.; Silva, M. C.; Whitney, K.; Bertucci, T.; Garza, J.; Boles, N. C.; Strang, K. H.; Mahali, S.; Marsh, J. A.; Chen, C.; Pugh, D. A.; Liu, Y.; Berlind, J. E.; Lai, J. D.; Goderie, S. K.; Chowdhury, R.; Lotz, S.; Lane, K.; Onanuga, K.; Karch, C.; Ichida, J.; Crary, J. F.; Haggarty, S. J.; Goate, A. M.; Temple, S.
Show abstract
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. At 2 months, mutant organoids show upregulated expression of MAPT, and glutamatergic signaling pathways and regulators including the RNA-binding protein ELAVL4. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function and build-up of tau and P-tau S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons of 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.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling 96%
- Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity 95%
- Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS. 95%
Similar papers in this journal
- Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1 95%
- Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model 95%
- CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions 94%
Similar papers in this journal
- Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity 96%
- Dissecting the molecular basis of human interneuron migrationin forebrain assembloids from Timothy syndrome 94%
- A reference induced pluripotent stem cell line for large-scale collaborative studies 94%
Similar papers in this journal
- Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans 95%
- Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer's disease, restores synapse integrity and memory in a disease mouse model 94%
- Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.