Wild-Type Tau Nerve Cell Model for Alzheimer's Drug Screening
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Solution Overview
Problem
Current methods for evaluating tau aggregation and its toxicity in neurodegenerative diseases, such as Alzheimer's, face challenges in reproducing pathophysiology caused by wild-type tau aggregation and require long-term cultures, making drug screening difficult.
Innovation Solution
A nerve cell model is developed by introducing an exogenous wild-type tau gene into human pluripotent stem cells, allowing for controlled expression and aggregation of tau, enabling the screening of drug candidates that suppress tau aggregation or cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutant tau is overexpressed to induce tau aggregation and cell death, then tau aggregation and cell death are reproduced, but the pathophysiology caused by wild-type tau aggregation cannot be reproduced
Solution Approach 1:
The patent changes the key parameter of tau protein type from mutant to wild-type, and controls the expression level parameter to achieve aggregation. This allows reproduction of pathophysiology while maintaining versatility across different tau scenarios.
Solution Approach 2:
The patent uses inducible expression systems to dynamically control tau protein expression levels in wild-type nerve cells, allowing the system to transition from non-aggregating to aggregating states as needed for different experimental purposes.
2Reliability
If tau aggregation promoting agents are added to overexpressed mutant tau to induce aggregation, then tau aggregation and cell death are induced, but it is difficult to evaluate the phenotype of tau alone since the agent itself is toxic
Solution Approach 1:
The patent extracts and removes the tau aggregation promoting agent from the experimental system, relying solely on wild-type tau overexpression to induce aggregation. This eliminates the toxic side effects of the agent while maintaining the ability to study tau phenotype independently.
3Reliability
If human pluripotent stem cell-derived nerve cells are used to reproduce tau aggregation and cell death, then pathophysiology is reproduced, but a long-term culture is required making drug screening difficult
Solution Approach 1:
The patent performs preliminary action by pre-differentiating human pluripotent stem cells into nerve cells and pre-establishing the tau expression system before drug screening begins. This allows the cells to be ready for high-throughput screening without requiring long-term culture during the screening process itself.
4Speed
If additional toxic agents are used to induce tau aggregation, then aggregation can be promoted, but the toxicity interferes with evaluating tau-related pathologies
Solution Approach 1:
The patent changes the mechanism of aggregation induction from chemical agent-mediated to protein overexpression-mediated, adjusting the expression level parameter to control aggregation speed without introducing external toxic agents that would interfere with pathology evaluation.
Data Source
AI summary
An object of the present invention is to provide a nerve cell in which tau aggregation and cell death are caused; a screening kit and a screening method, in which the nerve cell is used; a drug candidate substance obtained by the screening method; a human pluripotent stem cell for producing the nerve cell; and a method of producing the nerve cell.There is provided a nerve cell having an introduced exogenous wild-type tau gene.