Efficacy and Safety of a Brain-Penetrant Biologic TNF-alpha Inhibitor in Aged APP/PS1 Mice

Tumor necrosis factor alpha (TNF-alpha) plays a vital role in Alzheimer's disease (AD) pathology, and TNF-alpha inhibitors (TNFIs) modulate AD pathology. We fused the TNF-alpha receptor (TNFR), a biologic TNFI that sequesters TNF-alpha, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood-brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (A beta) 1-42, soluble-oligomeric A beta, and microgliosis; however, only TfRMAb-TNFR reduced A beta peptides, Thioflavin-S-positive A beta plaques, and insoluble-oligomeric A beta and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematologyor iron-dysregulation in aged APP/PS1 mice.