Inflammation plays an important role in the progression of Alzheimer’s disease. Several genetic factors modulate inflammation and have the potential to provide insight into novel treatment strategies. Modifying brain inflammatory responses is one important mechanism by which apolipoprotein E protein isoforms may modify susceptibility and progression of AD. The APOEgene provides instructions for making apolipoprotein E, which combines with fats or lipids in the body to form molecules called lipoproteins responsible for packaging cholesterol and other fats and carrying them through the bloodstream. There are different versions or alleles of the APOE gene, and the APOE4allele is associated with increased risk of Alzheimer’s disease. In this project, there has been the development of a therapeutic peptide, CN-105, that mimics the adaptive, anti-inflammatory and neuroprotective function of the protein. This therapeutic peptide was chosen from a library of APOE mimetic compounds based on its safety, efficacy in preclinical models, penetration of the central nervous system and ability to hit the target. Chronically administering CN-105 in a mouse model of AD that included the APOE4 allele improved brain pathology and learning and memory performance. The researchers observed a strong sex effect—female animals had significantly more advanced pathology. The next phase of this project will focus on sex differences in order to understand the factors that might inform early clinical trials. CN-105 has received investigational new drug approval, and it has completed Phase 1 clinical studies in which it demonstrated linear pharmacokinetics and safety. This therapeutic intervention has the potential for clinical translation in AD.
Increasing evidence suggests that brain inflammation plays an important role in mediating progression of Alzheimer’s disease (AD). In particular, it has been established that apolipoprotein E (APOE) plays a critical role in mediating neuroinflammation and disease pathology. We have developed specific APOE-based peptides that are rationally derived from the receptor-binding region of this protein, and we have demonstrated that these compounds are well tolerated, cross the blood-brain barrier, and reduce brain inflammation in preclinical models of AD and acute brain injury. We now test the hypothesis that chronic infusion of CN-105 is well tolerated, and reduces progression of pathology in a clinically relevant animal model of AD.