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An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
The yeast protein Ure2p triggers Tau pathology in a mouse model of tauopathy
Lanxia Meng1, Congcong Liu1, Miao Liu1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Abstract:
The molecular mechanisms that trigger Tau aggregation in Alzheimer's disease (AD) remain elusive. Fungi, especially Saccharomyces cerevisiae (S. cerevisiae), can be found in brain samples from patients with AD. Here, we show that the yeast protein Ure2p from S. cerevisiae interacts with Tau and facilitates its aggregation. The Ure2p-seeded Tau fibrils are more potent in seeding Tau and causing neurotoxicity in vitro. When injected into the hippocampus of Tau P301S transgenic mice, the Ure2p-seeded Tau fibrils show enhanced seeding activity compared with pure Tau fibrils. Strikingly, intracranial injection of Ure2p fibrils promotes the aggregation of Tau and cognitive impairment in Tau P301S mice. Furthermore, intranasal infection of S. cerevisiae in the nasal cavity of Tau P301S mice accelerates the aggregation of Tau. Together, these observations indicate that the yeast protein Ure2p initiates Tau pathology. Our results provide a conceptual advance that non-mammalian prions may cross-seed mammalian prion-like proteins.
Insights
Yeast protein Ure2p from Saccharomyces cerevisiae seeds Tau aggregation, accelerating Alzheimer's disease (AD) pathology and cognitive decline in mice. This suggests non-mammalian prions can initiate human prion-like diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Mycology
Background:
- Alzheimer's disease (AD) pathogenesis involves Tau protein aggregation, but the initiating molecular mechanisms are unclear.
- Fungi, including Saccharomyces cerevisiae (S. cerevisiae), have been detected in AD patient brain samples, hinting at potential microbial involvement.
- The role of microbial proteins in seeding Tau pathology is an emerging area of investigation.
Purpose of the Study:
- To investigate the potential role of Saccharomyces cerevisiae protein Ure2p in initiating Tau aggregation and Alzheimer's disease (AD) pathology.
- To determine if Ure2p can act as a seed for Tau aggregation and induce neurotoxicity.
- To explore the impact of Ure2p and S. cerevisiae infection on Tau pathology and cognitive function in a mouse model.
Main Methods:
- In vitro experiments demonstrating Ure2p interaction with Tau and its ability to seed Tau aggregation.
- Assessment of Ure2p-seeded Tau fibril potency in seeding Tau and causing neurotoxicity.
- In vivo studies involving hippocampal injection of Ure2p-seeded Tau fibrils and Ure2p fibrils into Tau P301S transgenic mice.
- Intranasal administration of S. cerevisiae to Tau P301S mice to evaluate Tau aggregation and cognitive impairment.
Main Results:
- The yeast protein Ure2p directly interacts with Tau and facilitates its aggregation.
- Ure2p-seeded Tau fibrils exhibit enhanced seeding activity and neurotoxicity compared to pure Tau fibrils in vitro.
- Intracranial injection of Ure2p fibrils into Tau P301S mice promoted Tau aggregation and led to cognitive impairment.
- Intranasal S. cerevisiae infection accelerated Tau aggregation in Tau P301S mice.
Conclusions:
- The yeast protein Ure2p can initiate Tau pathology, suggesting a novel mechanism for Alzheimer's disease (AD) pathogenesis.
- Non-mammalian prions, like Ure2p, may cross-seed mammalian prion-like proteins such as Tau.
- These findings provide a conceptual advance in understanding the interplay between microbial agents and neurodegenerative diseases.
