期刊
CELL
卷 184, 期 17, 页码 4547-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.07.003
关键词
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资金
- Tau Consortium
- Rainwater Charitable Foundation
- NIH [AG046374, NS110890, R01AG054008, R01NS095252, 2R01NS097850]
- CurePSP
- MGH Research Scholars Program
- Association for Frontotemporal Degeneration (AFTD)
- BrightFocus Foundation
- Farrell Family Alzheimer's Disease Research Fund
- NIH/NINDS [R35 NS097277]
- NIH/NIA [R01 AG056293]
- Department of Defense [W81XWH-21-10168, W81XWH-20-1-0424, W81XWH-21-1-0131]
- Harrington Discovery Institute
- CIRM, the ALS Association
- John Douglas French Alzheimer's Foundation
- ADDF, the New York Stem Cell Foundation
- Amgen postdoctoral fellowship
- NIH NINDS/NIA [F31NS117075]
- Empire State Stem Cell Fund (NYSTEM) through New York State Department of Health contract [C029158]
Frontotemporal dementia (FTD) caused by MAPT mutation leads to tau accumulation and glutamatergic neuronal death. Using human iPSC-derived cerebral organoids, this study identified molecular changes preceding neurodegeneration, highlighting glutamate signaling pathways as potential therapeutic targets for FTD.
Frontotemporal dementia (FTD) because of 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 because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. 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 as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
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