ArticleCell & bioscience2022
Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway.
Article in Cell & bioscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 7 citations in OpenAlex.
- Glucosamine links hyperglycemia to mTORC1 activation and glucose toxicity in diabetes.JCI insight · 2026Article
- Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.Clinical interventions in aging · 2026Review
- APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.International journal of biological sciences · 2026Article
- Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.EMBO molecular medicine · 2025Article
- CRISPR/Cas9 and iPSC-Based Therapeutic Approaches in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Clearance of beta-amyloid and tau aggregates is size dependent and altered by an inflammatory challenge.Brain communications · 2025Article
- The role of PI3K signaling pathway in Alzheimer's disease.Frontiers in aging neuroscience · 2024Review
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11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundThe mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer's disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer's disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue.
methodsWe generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining.
resultsThrough comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons.
conclusionWe demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD.
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