β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• G protein-coupled receptors (GPCRs) are implicated in Alzheimer's disease (AD) pathogenesis.
• The precise mechanisms by which diverse GPCRs influence amyloid-beta (Aβ) and tau pathology remain incompletely understood.
• GPCRs signal through β-arrestin scaffolding complexes, mediating desensitization and downstream events.

Purpose of the Study:

• To investigate the role of β-arrestin1 as a convergence point for GPCR-mediated tau pathogenesis.
• To determine if β-arrestin1 levels are altered in human tauopathy brains.
• To explore the therapeutic potential of targeting β-arrestin1 in tauopathies.

Main Methods:

• Utilized PS19 mouse models of tauopathy.
• Assessed β-arrestin1 levels in human Frontotemporal lobar degeneration with tau pathology (FTLD-tau) brains.
• Conducted biochemical and cellular studies to elucidate the molecular mechanisms of β-arrestin1 action.
• Investigated the impact of ARRB1 (gene encoding β-arrestin1) reduction on tauopathy and cognitive function.

Main Results:

• β-arrestins are essential for β2-adrenergic receptor (β2AR) and metabotropic glutamate receptor 2 (mGluR2)-mediated tau pathology.
• β-arrestin1 levels are elevated in FTLD-tau patient brains.
• Increased β-arrestin1 exacerbates tauopathy, while reducing ARRB1 alleviates tauopathy, synaptic dysfunction, and cognitive impairments in PS19 mice.
• β-arrestin1 destabilizes microtubules and impairs p62/SQSTM1 autophagy flux, promoting pathogenic tau accumulation.

Conclusions:

• β-arrestin1 acts as a critical mediator linking GPCR signaling to tau pathogenesis.
• Elevated β-arrestin1 is a key driver of tauopathy in FTLD-tau.
• Targeting β-arrestin1 represents a promising therapeutic strategy for tauopathies, including Alzheimer's disease.