PS19 Mouse Model for Tau Targeted Drug Development

At 9 months of age, PS19 mice normally show reduced motor strength, such as reduced grip strength, linked to tau pathology. However, more severe symptoms like hindlimb paralysis typically manifest between 10 and 12 months. This timeline aligns with progressive tau pathology and neuroinflammation affecting the motor system.

PS19 mice most closely model frontotemporal lobar degeneration (FTLD) with tau pathology, especially FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) caused by the P301S tau mutation. However, due to their widespread, robust, and progressive tau pathological profile, these mice can also provide insights into tau pathology relevant to Alzheimer’s disease and other tau-related neurodegenerative disorders.

In PS19 mice, several behavioral characteristics are observed after disease onset: 

• Hyperactivity: Increased locomotion is commonly observed, especially from 9 months as pathology advances.
• Anxiety-like behaviors: Reduced exploration in open-field and elevated plus maze tests, though results can vary by protocol.
• Cognitive deficits: Impaired memory and learning appear by 6 months, seen in tasks like the Morris water maze and novel object recognition.
• Motor impairments: Declines in strength, coordination, and balance emerge later, aligning with tau pathology progression.
• Additional signs of pathology: Advanced stages may include weight loss, lower body temperature, and increased frailty.

In PS19 mice, the P301S mutation is driven by a strong, constitutive mouse prion promoter, resulting in widespread tau pathology and neuroinflammation across multiple brain regions. This differs from other tauopathy mouse models, such as JNPL3, where pathology remains regionally restricted to the spinal cord and brainstem.  

Additionally, PS19 mice show more progressive tau pathology that correlates with both motor and cognitive deficits, making it useful for studying later-stage tauopathy and tau spreading across multiple brain regions. In contrast, other tauopathy models like rTg4510 mice show earlier tau pathology at 2-3 months, but less prominent motor deficits making it useful for early-stage tauopathy intervention studies.

• Faster induction and propagation of tau pathology 
• Reproducible induction of tau phosphorylation and misfolding 
• Closer recapitulation of key features of tau transmission, aggregation, and neurodegeneration relevant to human tauopathies
• More uniform development of cognitive and motor deficits
• More controlled and synchronized testing of tau-targeting therapies

Typically, drug efficacy studies using PS19 mice include group sizes of around 10 to 15 mice per treatment group to ensure sufficient statistical power while accounting for variability in pathology and phenotype expression. However, larger numbers may be necessary depending on the study design and variability.

There are a range of locomotor tests that can be performed to assess neuromuscular function in PS19 mice, including: 

• Grip strength test
• Open field test  
• Rotarod test  
• Walking/gait analysis
• Clinical and frailty scoring

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Alzheimer's Disease: a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is associated with the accumulation of amyloid-beta plaques and tau tangles in the brain, and loss of neurons and synapses in the cerebral cortex and subcortical regions 

Astrogliosis: the proliferation and hypertrophy of astrocytes, a type of glial cell, in response to brain injury or disease, often observed in neurodegenerative diseases. 

Brain Atrophy: reduction in volume or thickness of the entire brain or regions of the brain. 

Cognitive Impairment: a decline in cognitive function, including memory, thinking, and reasoning skills. 

Cytokine: a protein that serves as a signalling molecule among immune system cells. Cytokines are classified into interleukins, interferons, tumour necrosis factors (TNF), chemokines, colony-stimulating factors, and transforming growth factors. Depending on their role in the immune response, cytokines can be categorized as pro-inflammatory or anti-inflammatory. 

ELISA (Enzyme-Linked Immunosorbent Assay): a commonly used analytical biochemistry assay that detects the presence of a ligand (e.g. protein) in a liquid sample using antibodies directed against the ligand of interest.  

Frontotemporal Dementia (FTD): a group of neurodegenerative disorders characterized by progressive damage to the frontal and/or temporal lobes of the brain. This damage leads to a variety of symptoms that can include changes in personality, behavior, and language abilities. FTD is distinct from other types of dementia, such as Alzheimer's disease, in that it often affects younger individuals (typically between the ages of 45 and 65) and presents with early and prominent changes in social behavior, executive function, and language, rather than memory loss. The three main subtypes of FTD are Behavioral variant FTD (bvFTD), Non-fluent variant primary progressive aphasia (nfvPPA) and Semantic variant primary progressive aphasia (svPPA). 

Gliosis: the proliferation and hypertrophy of glial cells, in response to brain injury or disease, often observed in neurodegenerative diseases. 

Immunohistochemistry (IHC): a laboratory technique to rapidly identify specific proteins in cells and tissues. IHC capitalizes on the ability of antibodies to target specific proteins, and then utilizes a sandwich of secondary antibodies and detection reagents to identify and localize the protein of interest in tissue sections at the microscopic level. 

Magnetic Resonance Imaging (MRI): a non-invasive imaging modality that uses magnetic fields and radiofrequency (RF) pulses to generate images. 

Neurodegeneration: a complex, multifactorial process resulting in the loss of neurons.  

Neurofibrillary Tangles: abnormal accumulations of tau inside neurons. In healthy neurons, tau proteins help stabilize the structure of microtubules, in certain neurodegenerative conditions, such as Alzheimer's disease, tau proteins become hyperphosphorylated, causing them to clump together and form twisted, thread-like structures known as tangles.   

Neuroinflammation: an inflammatory response within the central nervous system (CNS), primarily involving the activation of microglia and astrocytes. This process can be triggered by various factors, including infections, traumatic brain injury, toxic metabolites, and autoimmune diseases.    

Preformed Fibril (PFF): recombinant, monomeric proteins (e.g. alpha-synuclein) that are incubated under specific conditions to generate aggregated, misfolded fibrils. 

Reactive Astrocytes: umbrella term for astrocytes adopting one of many possible molecular states as a response to pathological conditions in the CNS, as part of ‘reactive astrogliosis’. Defined by Escartin et al. (Escartin, 2021) in a consensus statement. 

Reactive Microglia: microglia that are responding to or reacting to a particular condition. The name was proposed by Paolicelli et al. (Paolicelli, 2022) in lieu of the discouraged term “activated” microglia, emphasizing that microglia can have many different “reactive states” in health and disease.  

Spatiotemporal Pattern: a pattern with both spatial and time components.  

Tau: a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and corticobasal degeneration.