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 &#x3b2;-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid &#x3b2; (sA&#x3b2;) peptide is converted into highly toxic oligomeric A&#x3b2; and fibrillar A&#x3b2; 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&#x3b2; 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&#x3b2; or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic A&#x3b2; 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&#x200a;=&#x200a;0.0001) and A&#x3b2;40/42 levels, as well as reduced A&#x3b2; oligomer levels. This type of immunomodulation has the potential to be a universal &#x3b2;-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases.