Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Tau post-translational modifications (PTMs) are implicated in Alzheimer's disease (AD) pathogenesis.
• Caspase-mediated tau cleavage is a key event in neurodegeneration, but its precise role remains unclear.
• Understanding tau cleavage mechanisms is crucial for developing AD therapeutics.

Purpose of the Study:

• To investigate the role of proteasome impairment in cleaved tau accumulation.
• To elucidate the impact of cleaved tau on neuronal activity and network function.
• To connect proteostasis, tau cleavage, and synaptotoxicity in the context of AD.

Main Methods:

• Utilized models to study tau cleavage and its consequences.
• Assessed tau accumulation at the post-synaptic density (PSD).
• Measured neuronal firing and network burst initiation.

Main Results:

• Proteasome impairment leads to cleaved tau (D421) accumulation at the PSD.
• Cleaved tau impairs neuronal firing and network burst initiation.
• Neuronal activity modulates cleaved tau accumulation.

Conclusions:

• Reduced neuronal activity coupled with proteasome dysfunction drives cleaved tau accumulation at the PSD.
• Cleaved tau at the PSD causes synaptotoxicity, contributing to AD progression.
• This study highlights the interplay between impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration in Alzheimer's disease.