Alzheimer’s Disease (AD) is expected to surge to frightening proportions world-wide, but there are no medications that efficaciously and safely stop disease progression. More than 200 clinical studies to diminish deposition of plaque-forming amyloid fibers in the brains of AD patients resulted in FDA approval of few anti-amyloid-β biologics, all with safety concerns and limited efficacy, likely because they target AD at a very advanced stage, where neuronal damage is irreversible. This prompted searches for therapeutic targets involved earlier in AD, particularly neuroinflammation leading to brain cell activation and death, for which there are no therapeutics. 

Neuroinflammation is mediated by inflammatory proteins produced by activated brain neurons. Age-related increases in neuronal receptors for these proteins (termed chemokines), and secretion by neuronal cells called microglia, contributes to increased production of amyloid-b and tau, major components of AD pathology. High levels of chemokine receptors are found in postmortem brains of AD patients, and their genetic deletion or blockade with brain-penetrable inhibitors, decreased production of amyloids, and ameliorated neuronal death in mouse AD models, supporting the hypothesis that these chemokine receptors are important early therapeutic targets. Antagonists of these receptors have not entered clinical trials or failed to show efficacy in other diseases. We have evidence that their failure was due to antagonist tolerance, a reduction in drug efficacy during prolonged treatment. We are addressing this by generating peptide and small molecule “biased” antagonists of chemokine receptors that avoid drug tolerance by inhibiting G-protein activation pathways but not receptor internalization/degradation. 

The goal of the proposed studies is to improve and contrast efficacy of “biased” chemokine receptor antagonists to “unbiased” antagonists in mouse AD models to demonstrate their efficacy and avoidance of drug tolerance. The project will aid the development of robust drugs that act against neuroinflammation in the early progressive phase of AD