Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific...

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Tauopathies like Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit sex-specific differences in prevalence and progression.
• The molecular underpinnings of these sex-specific variations in AD and FTD remain largely unknown.
• Single-cell transcriptomics in animal models offers a powerful approach to dissect cellular and sex-specific responses to AD pathology.

Purpose of the Study:

• To investigate sex-specific and sex-dimorphic transcriptomic alterations in various cell types within the THY-Tau22 mouse model of tauopathy.
• To examine the age-dependence of these transcriptomic changes from 7 to 17 months of age.
• To compare findings with other mouse models and human AD data for validation.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was performed on cortical tissue from male and female THY-Tau22 and wild-type mice at 7 and 17 months of age.
• Differential statistical analysis was used to identify sex-specific, sex-dimorphic, and sex-neutral gene expression and pathway changes.
• Results were validated against scRNA-seq data from the Tg2576 mouse model and human AD cortical samples.

Main Results:

• Significant sex-specific and sex-dimorphic gene expression changes were identified in neurons, microglia, astrocytes, and oligodendrocytes.
• Key affected pathways included neurotransmitter signaling, RNA processing, stress response, and protein degradation, with sex-dependent alterations across age.
• Age-dependent changes revealed consistent sex-dependent alterations in inflammatory response, protein homeostasis, and myelin maintenance pathways.
• The long non-coding RNA Malat1 showed conserved sex-specific changes across mouse models and human AD.

Conclusions:

• This study provides a detailed single-cell transcriptomic map of sex-linked and age-dependent changes in a tauopathy model.
• New insights into the interplay between aging, AD-like pathology, and sex have been uncovered.
• Identified sex-specific molecular changes, conserved across models and human AD, represent potential targets for developing sex-specific AD therapeutics.