Transgenic tau models

Tau protein and Alzheimer ’s disease

The hallmarks of Alzheimer’s disease seen in post-mortem brain tissue of patients are extracellular deposits of amyloid beta (plaques) and intracellular inclusions of the protein tau (tangles). Evidence from postmortem studies shows that tau pathology in Alzheimer’s disease starts in the entorhinal cortex and spreads throughout the brain. Recent PET studies show that the increase in tau pathology correlates well with the decline in cognitive function seen in Alzheimer’s disease patients.

Transgenic tau models

Transgenic tauopathy mouse models are widely used to study the efficacy of therapeutics that are aimed at preventing the initiation and/or spread of tau pathology. These models overexpress human tau with frontotemporal dementia-linked mutations throughout the nervous system, such as the P301L and P301S mutation. The overexpression of these mutated forms of tau result in a global induction of tau pathology that can be visualized with antibodies that recognize phosphorylated tau proteins such as the antibody AT8.

Tau pathology and motor function deficits

The global expression of transgenic tau protein in mouse models leads to various behavioral changes. High expression of toxic tau proteins in the brain stem and spinal cord lead to strong motor function impairments. For instance, the grip strength of mice expressing tau with a P301S mutation progressively decreases from 14 weeks of age onwards. Less aggressive development of pathology is seen in mice that express tau with a P301L mutation. At 6 months of age, subtle but significant changes in gait and foot print size measured using the Catwalk system indicate fine motor skill deficits. By 10 month or older, these mice show profound motor function deficits.

Biomarkers

For immunohistochemistry (IHC) we use the anti phopho-tau antibody to detect early signs of tau pathology. For more advanced tau pathology, we use thioflavin-S staining of intracellular filamentous tau inclusions. Besides these classical markers of pathology, we can analyze effects on neuroinflammation and we perform various biochemical analyses including ELISA.

Preclinical proof of concept studies at Sylics

The robustness of tau pathology and behavioral changes seen in transgenic tau models make them suitable models for drug discovery studies. Typical proof of concept studies at Sylics employ chronic administration of the therapeutic substance, longitudinal assessment of a protective effect on motor function and post-mortem analyses of biomarkers including a potential reduction in tau pathology. Sylics employs the transgenic JNPL3 tau model for fee-for-service studies. For further information on this model and possibilities, please contact us at info@sylics.com.