PS19 mice are genetically engineered models used in scientific research to investigate neurodegenerative diseases. They are a key tool for understanding tauopathies, a group of brain disorders characterized by the abnormal accumulation of tau protein.
The Genetic Basis of PS19 Mice
These mice are transgenic, carrying a human gene inserted into their genome. PS19 mice express a mutated form of the human microtubule-associated protein tau (MAPT) gene, which includes the P301S mutation.
The P301S mutation is found in some human forms of frontotemporal dementia. This mutation causes the tau protein produced in the mice to misfold and detach from microtubules, which are structures that help maintain cell shape and transport materials within neurons. The misfolded tau then aggregates into toxic clumps inside brain cells, disrupting normal neuronal function.
Modeling Human Tauopathies
The PS19 model is primarily utilized to study frontotemporal dementia (FTD). FTD often manifests as changes in personality, behavior, and language abilities.
The model also contributes to understanding aspects of Alzheimer’s disease, which features tau pathology alongside amyloid-beta plaques. Furthermore, PS19 mice are relevant for investigating other tau-related disorders, such as progressive supranuclear palsy, a rare neurological condition affecting movement, balance, and eye movements.
Disease Progression and Phenotype
PS19 mice develop observable characteristics, or phenotypes, as they age, mirroring features of human tauopathies. Around 6 to 9 months of age, these mice typically begin to exhibit early-onset motor deficits. These can include a clasping reflex where their hind limbs draw inward when suspended by the tail, along with reduced mobility and eventual hind limb paralysis.
As the disease progresses, often by 9 to 12 months of age, the mice can also develop cognitive impairments. These deficits manifest as difficulties with memory and learning tasks in behavioral tests. Such changes reflect the widespread neurodegeneration occurring in their brains.
Underlying these observable symptoms are significant pathological changes in the brain tissue. Neurofibrillary tangles (NFTs), which are aggregates of hyperphosphorylated tau, form extensively throughout various brain regions, including the hippocampus and cortex. There is also substantial neuronal loss in these areas, particularly in the CA1 region of the hippocampus, which is crucial for memory. Additionally, the brains of PS19 mice show signs of neuroinflammation, characterized by astrogliosis, an increase in reactive astrocytes, and microgliosis, an activation of microglial cells, both indicating an immune response to neuronal damage.
Role in Therapeutic Research and Discovery
Researchers extensively use PS19 mice to test potential treatments for tauopathies. These mice provide a living system to evaluate whether new compounds or genetic interventions can slow or halt the progression of tau-related neurodegeneration. Various therapeutic strategies have been investigated using this model.
Examples include the testing of antibodies designed to clear aggregated tau from the brain or prevent its spread. Small molecules that aim to inhibit tau aggregation or modify tau phosphorylation have also been evaluated. Genetic approaches, such as the use of antisense oligonucleotides (ASOs) to reduce the production of tau protein, are another area of active research. The predictable and relatively rapid disease progression in PS19 mice makes them valuable for screening potential drugs before advancing to human clinical trials.
Limitations of the PS19 Model
The PS19 mouse model has certain limitations. For instance, the aggressive, motor-dominant phenotype observed in these mice does not perfectly replicate the typical progression of all human tauopathies. While relevant to Alzheimer’s disease, the PS19 model’s primary motor symptoms differ from the initial cognitive decline often seen in human Alzheimer’s patients.
This model primarily focuses on tau pathology. Unless cross-bred with other mouse lines, PS19 mice do not spontaneously develop amyloid-beta plaques, another hallmark of Alzheimer’s disease. It therefore does not fully encompass the complex interplay between amyloid and tau pathologies. Despite this, the PS19 model is a valuable tool for studying the specific consequences of tau protein toxicity in neurodegeneration.