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

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high beta-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid beta (sA beta) peptide is converted into highly toxic oligomeric A beta and fibrillar A beta 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 sA beta 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 A beta or other human proteins. We show that the pA beta ri peptide through conformational mimicry induces a humoral immune response not only to the toxic A beta 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 A beta 40/42 levels, as well as reduced A beta oligomer levels. This type of immunomodulation has the potential to be a universal beta-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases.