Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model.

Area of Science:

• Neuroscience
• Genomics
• Neurodegenerative Diseases

Background:

• Neurodegenerative disorders like Alzheimer's disease (AD) involve gradual neurobiological changes years before clinical diagnosis.
• Understanding the progression of brain dysfunction is crucial for developing effective treatments.

Purpose of the Study:

• To longitudinally characterize behavioral, morphological, and transcriptomic changes in a P301S transgenic mouse model of tauopathy.
• To elucidate the temporal relationship between molecular alterations and the onset of neurodegenerative symptoms.

Main Methods:

• Longitudinal behavioral testing (cognitive and social deficits).
• Morphological analysis of neuronal dendritic arborization (hippocampal and PFC neurons).
• Genome-wide transcriptomic analysis to identify gene expression changes.

Main Results:

• P301S mice showed cognitive deficits by 3 months and social deficits by 5-6 months.
• Reduced dendritic arborization was observed in hippocampal neurons (3 months) and PFC neurons (9 months).
• Early synaptic gene upregulation at 3 months was followed by widespread downregulation in PFC and hippocampus by 9 months.

Conclusions:

• Time-dependent gene expression changes in tauopathy models contribute to progressive neuronal structural and functional alterations.
• These molecular and cellular changes precede and likely drive the manifestation of behavioral symptoms in tauopathies.
• This study provides insights into the early pathogenesis of Alzheimer's disease and related tauopathies.