Plasma MicroRNAs Are Altered Early and Consistently in a Mouse Model of Tauopathy

Area of Science:

• Neuroscience
• Molecular Biology
• Biomarker Discovery

Background:

• Tauopathies are neurodegenerative diseases characterized by pathological tau protein accumulation.
• Disease onset is preceded by a lengthy pre-symptomatic phase, representing a critical window for therapeutic intervention.
• Identifying pre-symptomatic biomarkers is crucial for early diagnosis and treatment of tauopathies.

Purpose of the Study:

• To profile blood plasma microRNAs in a mouse model of tauopathy to identify biomarkers of pre-symptomatic disease.
• To evaluate the diagnostic accuracy of candidate microRNAs for detecting early-stage tauopathy.
• To investigate the biological pathways targeted by identified microRNAs.

Main Methods:

• Small RNA sequencing was used for global microRNA profiling in hTau mice and wild-type controls at 16 and 53 weeks of age.
• TaqMan RT-qPCR was employed for validation of selected microRNAs.
• Area under the receiver operating characteristic curve (AUC) was calculated to assess discriminative accuracy.

Main Results:

• Three microRNAs (miR-150-5p, miR-155-5p, miR-375-3p) were significantly down-regulated in pre-symptomatic 16-week-old hTau mice.
• These microRNAs maintained their down-regulated levels in older mice with cognitive deficits and neuropathology.
• High discriminative accuracy (AUC 0.95-1) was observed for these microRNAs in distinguishing between hTau and wild-type mice.

Conclusions:

• Circulating microRNAs, specifically miR-150-5p, miR-155-5p, and miR-375-3p, are promising biomarkers for pre-symptomatic tauopathy.
• These microRNAs reflect early neuropathological changes and converge on pathways involved in neuronal signaling and tau phosphorylation.
• Further validation in human cohorts is warranted for clinical application in early tauopathy detection.