[O4–06–04]: PROTECTIVE EFFECTS OF A BRAIN‐PENETRATING BIOLOGIC TNF‐ALPHA INHIBITOR IN A MOUSE MODEL OF ALZHEIMER's DISEASE

Tumor necrosis factor alpha (TNF-α) driven processes are involved at multiple stages of Alzheimer's disease (AD) pathophysiology and disease progression. Biologic TNF-α inhibitors (TNFIs) are the most potent class of TNFIs but cannot be developed for AD since these macromolecules do not cross the blood-brain barrier (BBB). A BBB-penetrating TNFI was engineered by the fusion of the extracellular domain of the type II human TNF receptor (TNFR) to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as the cTfRMAb-TNFR fusion protein. The cTfRMAb domain functions as a molecular Trojan horse, binding to the endogenous TfR on the mouse BBB, and ferrying the biologic TNFI across the BBB via receptor-mediated transcytosis. 6 month old male APPswe, PSEN1dE9 (APP/PS1) transgenic mice were treated with either saline (n=13), the cTfRMAb-TNFR fusion protein (n=12) or etanercept (non-BBB-penetrating TNFI; n=11) 3 days/week intraperitoneally. After 12 weeks of treatment, recognition memory was assessed using the novel object recognition task, mice were sacrificed, and brains were assessed for Aβ load, neuroinflammation and BBB disruption. The cTfRMAb-TNFR fusion protein treatment caused a significant reduction in brain Aβ burden (both Aβ peptide and plaque), neuroinflammatory marker ICAM-1, and a BBB disruption marker, parenchymal IgG, and improved recognition memory in the APP/PS1 mice. Chronic treatment with the cTfRMAb-TNFR fusion protein, a BBB-penetrating biologic TNFI, offers therapeutic benefits by targeting Aβ pathology, neuroinflammation and BBB-damage, overall improving recognition memory in a transgenic mouse model of AD.