Wild-Derived Humanized Mouse Models for Human-Relevant AD Pathology
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Solution Overview
Problem
Existing transgenic mouse models expressing human amyloid precursor protein (APP) and presenilin 1 (PSEN1) inadequately recapitulate the widespread neurodegeneration and regional brain atrophy seen in Alzheimer's disease, with limited genetic diversity and biased amyloid deposition, failing to capture human-relevant AD pathology.
Innovation Solution
Development of wild-derived humanized mouse models expressing human APP, mutated PSEN1, and human apolipoprotein E (APOE), particularly APOE4, on genetically diverse backgrounds like WSB/EiJ, CAST/EiJ, and PWK/PhJ strains, allowing for more clinically relevant AD pathogenesis studies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If transgenic mouse models expressing human APP and PSEN1 are used, then Alzheimer's disease pathogenesis can be studied in vivo, but the models inadequately recapitulate widespread neurodegeneration and regional brain atrophy
Solution Approach 1:
The patent changes the genetic background parameter from limited laboratory strains (C57BL6/J) to wild-derived strains with high genetic diversity. This parameter change enables the model to better recapitulate human AD pathology, including widespread neurodegeneration and regional brain atrophy, while maintaining the transgenic expression of human APP and PSEN1.
Solution Approach 2:
The patent creates a composite genetic model by combining wild-derived mouse background (providing genetic diversity) with human transgenic genes (APP and PSEN1). This composite approach allows the model to exhibit both the genetic variability seen in human populations and the specific Alzheimer's disease pathology driven by human amyloid processing enzymes.
2Ease of manufacture
If transgenic mouse models are made on limited background strains like C57BL6/J, then the models are easier to generate and maintain, but they exhibit excessive parenchymal amyloid deposits greater than those seen in human patients
Solution Approach 1:
The patent changes the strain background parameter from C57BL6/J to wild-derived strains (e.g., WSB/EiJ, CAST/EiJ, PWK/PhJ). This change reduces the excessive amyloid deposit burden to levels more comparable to human patients, improving the accuracy of the model despite increased complexity in generation and maintenance.
3Productivity
If existing transgenic mouse models expressing APP are used, then they provide a platform for AD research, but they are limited in capacity to recapitulate human-relevant AD pathology due to limited genetic diversity
Solution Approach 1:
The patent creates a composite model combining wild-derived genetic background with human APP transgenic elements. This composite approach maintains research utility while improving human-relevance by capturing the interaction between human amyloid processing and diverse genetic backgrounds, enabling exploration of neuroinflammatory responses and amyloid interactions more representative of human disease.
Data Source
AI summary
The present disclosure provides wild-derived mouse models that comprise a nucleic acid encoding a human amyloid precursor protein (APP), a nucleic acid encoding a mutated human presenilin (1) protein (PSEN1), and in some embodiments, a human apolipoprotein E (APOE), or human amyloid beta and human tau. These mouse models are useful, for example, for Alzheimer's disease studies.