Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Neuropathology
• Animal Models

Background:

• Tau pathology in the substantia nigra is a hallmark of tauopathies with Parkinsonian features.
• Understanding tau's role in this region is crucial for developing effective treatments.
• Adeno-associated virus (AAV) vectors enable targeted gene delivery for studying neurodegeneration in vivo.

Purpose of the Study:

• To characterize a novel mouse model of tau-related neurodegeneration in the substantia nigra.
• To investigate the effects of human wild-type tau expression in the midbrain, specifically targeting dopaminergic neurons.
• To establish a tool for preclinical studies of tauopathies with Parkinsonian features.

Main Methods:

• Unilateral stereotaxic injection of AAV vectors overexpressing human tau (AAV-Tau) or a control vector into the substantia nigra pars compacta of young and aged mice.
• Weekly assessment of motor deficits including hindlimb clasping and nesting.
• Evaluation of locomotor asymmetry, motor coordination, and balance using behavioral tests (tail suspension swing, cylinder, rotarod).
• In vivo anatomical MRI scans to assess regional neuroanatomical volumes at 12 weeks post-injection.

Main Results:

• AAV-Tau injected mice exhibited progressive motor dysfunction, including locomotor asymmetry, impaired coordination, and hindlimb clasping.
• Motor deficits were more severe in aged mice compared to young mice.
• Significant reduction in regional brain volumes (midbrain, striatum) was observed in the hemisphere ipsilateral to the AAV-Tau injection.

Conclusions:

• The AAV-Tau mouse model demonstrates early motor deficits and brain atrophy, making it a valuable tool for preclinical research.
• This model can accelerate the development of disease-modifying therapies for tauopathies with Parkinsonian features.
• The model is suitable for studying conditions like Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD).