Taleen Hanania, Herman Fernandes, Mei Kwan, Jose Beltran, John Shea, Afshin Ghavami
Objectives: rTg4510 mice conditionally express mutant human Tau in various forebrain regions using Tet-off expression system. This model recapitulates tau pathology observed in AD with age-dependent neuronal loss resulting in cognitive impairment. The objective of the study was to assess age associated behavioral, electrophysiological, and biomarker changes.
Methods: Female tTA and rTg450 mice were purchased from JAX labs. Locomotor activity was assessed in the open field chambers. Cognitive performance was assessed using the Y maze and Morris water maze tests. Basal synaptic transmission and LTP were assessed by extracellular field potential recording at the Schaffer collateral-CA1 pyramidal. Nf-L levels were measured by Quanterix and inflammatory and Tau by MSD technologies.
Results: rTg4510 mice showed hyperactivity starting at 4 months of age. Cognitive deficits were seen in the Morris water maze during acquisition and probe tests. Although spontaneous alterations were decreased in rTg4510 mice, number of entries were increased indicating hyperactivity. rTg4510 mice showed elevated tau levels in plasma and CSF at 3 and 6 months of age, with an 11-fold increase in CSF but only 2-fold increases in plasma at 6 months. Plasma and CSF Nf-L levels were increased in rTg4510 mice at 6 months only. Among the inflammatory markers assessed, only IL-1b was increased in CSF at three months of age. Basal synaptic transmission and LTP were impaired at 6 months of age. Behavioral and electrophysiological effects and levels of all biomarkers were restored by Doxycycline (Dox) treatment.
Conclusions: Neuropathological changes in rTg4510 mice appear as early as 3 months of age and become widespread by 6 months. Behavioral and biomarker changes can be reversed by Dox treatment, making this model ideal for evaluating Alzheimer’s disease therapies.