P3‐002: Overexpression of tau in the mouse forebrain using adeno‐associated virus (AAV) leads to tau hyperphosphorylation, formation of neurofibrillary tangles and neurodegeneration

Abstract

The use of viral vectors provides an alternative approach to replicate cardinal features of tauopathies in the mouse brain and complement existing transgenic mouse models. AAV vectors were designed for overexpression of various forms of human tau, and injected in the lateral ventricle to induce tau pathology in the mouse forebrain. We generated AAV constructs encoding various forms of the human tau protein under the control of the mouse PGK-1 promoter. Two wild-type versions of human tau (tau4R0N, tau3R0N) were compared with a tau mutant causing frontotemporal dementia (tau4R0N-P301S), and an aggregation-deficient mutated variant (tau4R0N-I277P/I308P). AAV serotype 6 vectors were bilaterally injected in the lateral ventricles of mouse neonates using a stereotactic system (ICV injections). In order to compare the kinetic of the pathology induced by these different forms of tau, the injected mice were analyzed at 6, 9 and 24 weeks post-injection. We monitored by histological analysis the deposition of phosphorylated and aggregated forms of tau in the mouse cortex and hippocampus, as well as the induced neurodegeneration. Changes in animal motor performance were assessed behaviorally (rotarod test). AAV-injected mice displayed a clear neuronal accumulation of human tau protein in various brain regions including the cerebral cortex, hippocampus and brainstem. Expectedly, high levels of human tau were predominantly found in brain regions lining the ventricular system. At an early time point, we showed significant accumulation of hyperphosphorylated tau protein (AT8 staining) in the neuronal cell bodies as well as in the dendritic compartment. Tau aggregation was revealed by immunohistochemistry using a conformational antibody and confirmed by Gallyas staining at later time points. A significant neurodegeneration was also observed, mostly in the region of the cerebral cortex close to the site of vector injection. In addition, the motor performance of the AAV-injected mice became progressively impaired. ICV delivery of AAV vectors in mouse neonates can efficiently induce neuronal tau expression in the forebrain. The resulting accumulation of human tau leads to a robust neuropathology mainly characterized by tau aggregation. The observed pathology correlates with acute neurodegeneration and progressive impairment of animal motor behavior.