Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Immunotherapy

Background:

• Trans-synaptic tau transmission drives Alzheimer's disease (AD) pathology.
• Current immunotherapies struggle to target tau species within the synaptic cleft.
• Limitations include antibody selectivity, CNS availability, and synaptic access.

Purpose of the Study:

• To develop a novel strategy for targeting pathogenic tau species at the synapse.
• To overcome limitations of existing immunotherapies for AD.

Main Methods:

• Purified synaptosomes from AD and control patients.
• Utilized phospho-proteomics to identify tau epitopes in post-synaptic terminals.
• Developed a synaptic-chimeric antibody receptor (synCAR) by fusing PHF1 scFv with neurolignin-1 (NLGN1) and delivered via AAV9.

Main Results:

• Identified 17 phospho-tau epitopes enriched in AD post-synaptic fractions, including PHF1 (pS396/pS404).
• PHF1 synCAR expressed effectively at the synaptic membrane in murine and hiPSC neuronal models without affecting viability.
• PHF1 synCAR targeting of pathogenic tau increased tau aggregation in seeded neurons by ~73%, indicating capture and concentration of tau seeds.

Conclusions:

• The study presents a novel mechanism for targeting proteins within the synaptic cleft or post-synaptic membrane.
• PHF1 synCAR offers an effective approach for isolating and identifying propagating tau species.
• This strategy holds potential for developing new AD therapeutics.