Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Synaptic plasticity is crucial for memory formation but is impaired in tauopathies like Alzheimer's disease (AD).
• Pathogenic tau accumulation in neurons obstructs synaptic plasticity, leading to memory loss, but the precise mechanism remains unclear.

Purpose of the Study:

• To elucidate how pathogenic tau inhibits synaptic plasticity and causes memory deficits.
• To identify the molecular targets and pathways involved in tau-mediated synaptic dysfunction.

Main Methods:

• Analysis of the plasticity-associated translatome in Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) neurons.
• Investigating the interaction between pathogenic tau and the translation initiation factor eIF4B.
• Assessing the impact of modulating tau-eIF4B interaction on dendritic protein synthesis and synaptic plasticity.

Main Results:

• FTLD-tau inhibits synaptic plasticity by blocking activity-dependent protein synthesis in neuronal dendrites.
• Pathogenic tau binds to eIF4B, causing its dissociation from the translation initiation complex and reducing its levels in dendrites.
• Restoring eIF4B levels or inhibiting the tau-eIF4B interaction rescued local protein synthesis and synaptic plasticity in FTLD-tau neurons.

Conclusions:

• Pathogenic tau binding to eIF4B disrupts the local synthesis of essential plasticity-related proteins.
• This disruption in protein synthesis impairs synapse strengthening and memory formation in tauopathies.
• Targeting the tau-eIF4B interaction presents a potential therapeutic strategy for memory loss in AD and related disorders.