SynCAR platform for capturing neuronal synaptic proteopathic seeds

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Synaptic proteins are crucial for neuronal function but implicated in the spread of neurodegenerative diseases.
• Existing technologies face limitations in identifying synaptic proteins in situ.
• Pathological proteins, like tau in Alzheimer's disease, can spread between synapses.

Purpose of the Study:

• To develop a novel tool for the in situ identification and modulation of synaptic proteins.
• To investigate the role of synaptic proteins in the prion-like spreading of pathological tau.
• To establish a platform for neurodegenerative disease research and drug development.

Main Methods:

• Construction of a modular synaptic chimeric antigen receptor (synCAR) by fusing a single-chain antibody fragment with neurolignin-1 (NLGN1).
• Application of the synCAR platform to capture pathogenic tau species at the synapse using the PHF1 antibody.
• Expression of the PHF1 synCAR in mouse primary and human neuronal tau seeding models.

Main Results:

• The synCAR platform successfully captured pathogenic synaptic tau species.
• Anchoring the tau antibody PHF1 to the synapse via synCAR enhanced tau aggregation.
• Concentration of pathological tau seeds at the synapse by synCAR likely increased aggregation.

Conclusions:

• The study presents the first method for isolating and modulating synaptic protein function in situ.
• The synCAR platform is a valuable tool for synaptic protein research.
• SynCAR technology holds promise for neurodegenerative disease drug development, particularly for Alzheimer's disease.