Mouse models have been extensively used to study the onset and development of neuronal diseases, and evaluate response to therapies. These models of neurodegenerative disease have been generated using multiple approaches including genetic engineering, pharmacological stimuli and seeding of disease cell lysates1.For example, several types of transgenic models of Alzheimer’s disease (AD) that focus on beta-amyloid (APP) or tau pathologies have been developed to study the pathophysiology of Alzheimer’s disease as well as other types of dementia. Parkinson’s disease model can be broadly segmented into 2 types – 1) pharmacological models where chemicals such as 6-hydroxydopamine are used to damage and destroy dopaminergic neurons or 2) transgenic models that have mutations in genes that are known to be associated with Parkinson’s disease. Despite the decades of work and billions of dollars spent on these models, it is evident that mouse models of neurodegenerative diseases are not fully representative of the disease state and do not recapitulate the overall disease phenotype1. There are several critical differences between human disease and modeling the disease in mice that limits the translatability of mouse model data to human patients such as the difference in biomarker endpoints and the physiological differences between mouse and human brains. The lack of physiologically relevant animal models that recapitulate an acceptable level of disease pathophysiology is one of the main reasons that no curative therapies have been developed for neurodegenerative diseases such as AD, Parkinson’s or ALS.
Despite the challenges, mouse models are critical tools for preclinical drug development, so, in an effort to improve the translatability, scientists are developing chimeric mouse models. Chimeric mice, as the name suggests, are developed by transplanting human cells into the mouse brain. The transplanted human cells are typically derived from induced pluripotent stem cells (iPSCs) that can be genetically modified if required2. A 2019 study from a Belgium research group demonstrated that ES cell derived cortical pyramidal neurons when injected into the mouse brain cortex with EGTA (to facilitate integration) were able to not only integrate but also migrate through the mouse cortex while remaining viable and functional2. A percentage of transplanted neurons were shown to respond to visual stimuli. This finding suggests that transplanting stem cell derived neurons into mouse brains could be a model to study neuronal plasticity and could even be a cell therapy-based strategy to reverse brain damage2.
There is a growing body of work on the development of chimeric mice to model specific disease states including Alzheimer’s disease. One of the earliest reports on the development of chimeric AD models was in 2017 where researchers transplanted iPSC derived neurons into the brains of AD mice3. Unfortunately, this strategy had limited success as the neurons died before the development of neurofibrillary tangles. A recent paper advanced the work by transplanting astrocytes derived from iPSCs of AD patients into a transgenic Alzheimer’s disease model4. The iPSC derived astrocytes expressed either ApoE3 that is not associated with AD or ApoE4 that is strongly associated with late onset of AD. The transplanted astrocytes integrated into the mouse brain and were shown to acquire human astrocyte specific morphologies that are different from rodent astrocytes. More interestingly, the transplanted human astrocytes responded to the A-beta deposits in the mouse AD model where some of the astrocytes became hypertrophic and others atrophied. Astrocyte hypertrophy is considered to be a defense against AD pathology while atrophy is a loss of function associated with aging and neurodegenerative disease. The presence of both hypertrophy and atrophy in the AD mouse brain suggests that a chimeric model could provide valuable insights into early AD development and this information is critical to develop therapies that can significantly delay, halt or even reverse early AD development. While these are early days, the data suggests that chimeric mice might be the next generation of mouse models to study the onset and development of complex neurodegenerative diseases such as Alzheimer’s disease.
References:
1https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/
2https://www.nature.com/articles/s41684-020-0477-5
3https://pubmed.ncbi.nlm.nih.gov/28238547/
4https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00487-8
