Interactions of Therapeutic Antibodies With Presynaptically-Released Misfolded Proteins in Neurodegenerative...

The spatial progression hypothesis of misfolded tau and alpha-synuclein proteins in Alzheimer's and Parkinson's Disease proposes the release of proteins from a presynaptic membrane followed by diffusion over the synaptic cleft and uptake by the postsynaptic membrane in the afferent neuron. A number of antibodies aiming to reduce this neuronal uptake by capturing these proteins in the extracellular space are currently in clinical development, so far without much success. For modeling the interaction between antibodies and misfolded proteins in the extremely small synaptic volume with only a few proteins navigating a crowded environment of transsynaptic proteins, traditional assumptions of ordinary differential equations (ODEs) break down. Here we use spatial Monte Carlo calculations of individual molecule trajectories in a realistic geometrical environment using the open-source software Mcell (mcell.org). For several different densities of transsynaptic proteins, we show that due to geometric constraints, less than 0.5% of the antibody in the brain interstitial fluid (ISF) can enter the crowded synaptic cleft. As a consequence, uptake of the seed-competent proteins is reduced by less than 10%, even at the highest concentration and for selective antibodies. Only the seed-competent protein that escapes the synaptic cleft (between 15% and 30%) is captured by the antibody. Given the extremely low penetrance of the antibodies, it is close to impossible for antibodies to interfere with the uptake mechanism that takes place in the synaptic cleft. These simulations using a detailed and realistic biological environment provide a possible explanation for the clinical trial failures of anti-tau and anti-αsynuclein antibodies.