BBB-ABP Fusion Protein Selectively Binds Amyloid-β Oligomers, Preventing In Vitro Neurotoxicity

Alzheimer's disease (AD) pathogenesis is strongly linked to soluble amyloid-β oligomers (Aβo), considered the most neurotoxic Aβ species. Current therapeutic strategies often struggle with effectively targeting these oligomers and overcoming the blood-brain barrier (BBB). This study builds on previous work identifying an amyloid-binding peptide (ABP) and its fusion to the BBB transporter FC5 and an Fc fragment, creating BBB-ABP constructs designed for enhanced brain penetration and selective Aβo engagement.

Researchers evaluated the in vitro functionality of BBB-ABP using ELISA and western blot overlay assays to confirm binding specificity. Functional assays were conducted in SH-SY5Y cells and primary neurons to assess Aβo sequestration and protection against Aβo-induced toxicity. Effects on synaptic activity were measured via multi-electrode arrays to determine if BBB-ABP could prevent Aβo-induced synaptic dysfunction.

The BBB-ABP fusion protein successfully retained its selective binding to Aβo, as confirmed by ELISA and western blot. It effectively prevented the interaction of Aβo with neuronal proteins and its binding to dendritic spines in live primary neurons. This protective action translated into a significant reduction in Aβo-induced toxicity. > BBB-ABP significantly reduced Aβo-induced toxicity in both SH-SY5Y cells and primary neurons, even under conditions of NMDA-induced stress. However, Aβ exposure itself did not significantly alter spontaneous synaptic activity in their model, which precluded the assessment of electrophysiological rescue by BBB-ABP.