Network analysis reveals strain-dependent response to misfolded tau aggregates

Area of Science:

• Neuroscience
• Genetics

Background:

• Mouse genetic background modulates amyloid and tau pathology in Alzheimer's disease (AD).
• Understanding the mechanisms of genetic influence on tau aggregate pathogenicity is crucial for AD modeling.

Approach:

• Induced tau aggregation in wild-derived mice (C57BL/6J, CAST/EiJ, PWK/PhJ, WSB/EiJ) by expressing MAPT (P301L).
• Performed RNA sequencing on mouse brains and measured tau seeding activity.
• Identified core, background-specific, and tau seeding-associated gene signatures.

Key Points:

• Distinct transcriptional signatures were identified based on mouse genetic background.
• Microglial response to tau seeds was elevated in CAST/EiJ and PWK/PhJ mice.
• Mouse genetic context significantly influences tau seeding.

Conclusions:

• Tau seeding precedes tau phosphorylation and aggregate spreading.
• Transcriptomic responses to tau and elevated tau seeds were observed in wild-derived mice.
• This study provides a valuable resource combining genetics, tau biosensor assays, and transcriptomics for AD research.