Therapeutic Targeting of Abnormal Conformation in Neurodegenerative Disease

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DESCRIPTION (provided by applicant): Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ¿-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms. None of the conformational diseases has an effective therapy; however, immunomodulation has shown great promise for both AD and prion diseases. Major problems with this approach include: the potential of toxicity from encephalitis (related to excessive cell mediated immunity), the immunological targeting of both the normal and abnormal A¿, the resistance of vascular amyloid to clearance, as well as tau related pathology not being specifically addressed. The central hypothesis of this proposal is that each of these limitations can be overcome by specific targeting of abnormal oligomer conformation and development of novel methods to prevent oligomer mediated toxicity. Our novel active immunomodulation approach uses a polymerized British amyloidosis (pABri) related peptide in a predominantly ¿-sheet, oligomeric form. We hypothesized that through "conformational mimicry" the polymerized ABri peptide could induce a conformation selective immune response that will recognize both A¿ and conformationally abnormal tau. This hypothesis is supported by preliminary data in an APP/PS1 AD mouse model. Such an immunostimulatory approach should have a reduced risk of inducing auto-immune complications as it is more specific to a pathological conformer and the immunogen has no sequence homology to any known mammalian protein/peptide. We also present preliminary data that short term treatment with monoclonal 6D11, an anti-PrP antibody, reverses behavioral deficits in an AD model APP/PS1 Tg mice. This antibody blocks the binding of A¿ oligomers to PrPC. We hypothesize that blocking the binding of A¿ oligomers and PrPC is a novel therapeutic strategy for AD. These complementary approaches will aim to both increase clearance of A¿ oligomers and specifically block their toxicity. PUBLIC HEALTH RELEVANCE: Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ¿-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms, which we plan to target by developing novel approaches to both increase their clearance and to reduce their toxicity.