Immunomodulation Targeting Abnormal Protein Conformation Reduces Pathology in a Mouse Model of Alzheimer's Disease

Abstract

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high b-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid b (sAb) peptide is converted into highly toxic oligomeric Ab and fibrillar Ab that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAb and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Ab or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Ab in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p,0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Ab40/42 levels, as well as reduced Ab oligomer levels. This type of immunomodulation has the potential to be a universal b-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases.