Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Tau protein aggregate deposition defines tauopathies like Alzheimer's disease.
• Toxic tau disrupts nuclear architecture, causing heterochromatin decondensation and retrotransposon activation.
• Retrotransposons, similar to retroviruses, can produce double-stranded RNA (dsRNA), a trigger for neuroinflammation.

Purpose of the Study:

• To investigate the role of pathogenic tau-induced retrotransposon activation in neurodegeneration and neuroinflammation.
• To determine if dsRNA is elevated in tauopathies and linked to tau pathology.
• To elucidate the causal relationship between tau, heterochromatin, retrotransposons, and dsRNA-mediated brain inflammation.

Main Methods:

• Analysis of postmortem human brain tissue from Alzheimer's disease and progressive supranuclear palsy patients.
• Examination of brains from tau transgenic mice.
• Utilizing a *Drosophila* model of tauopathy to study specific retrotransposons and dsRNA production.

Main Results:

• Elevated levels of dsRNA and dsRNA sensing machinery were observed in astrocytes of human AD/PSP brains and tau transgenic mouse brains.
• Specific tau-induced retrotransposons were identified in the *Drosophila* tauopathy model.
• Pathogenic tau and heterochromatin decondensation were found to causally drive dsRNA-mediated neurodegeneration and neuroinflammation.

Conclusions:

• Pathogenic tau induces heterochromatin decondensation, leading to retrotransposon activation.
• Activated retrotransposons generate inflammatory dsRNA in the adult brain.
• This dsRNA production is a key mediator of neurodegeneration and neuroinflammation in tauopathies.