Development of vaccination approaches for the treatment of neurological diseases

Several progressive neurodegenerative diseases share a common pathology: the accumulation of misfolded proteins within cells or neuropil of the brain. Characteristically, these misfolded proteins form organized beta-sheet-containing assemblies that have optical and biochemical properties of amyloid. Thus, the brain amyloidoses, Alzheimer's disease (AD), Parkinson's disease, and the prionoses or transmissible spongioform encelphalopathies (TSEs) all manifest putatively pathogenic misfolded proteins, suggesting that these proteins or their precursors may be targets for therapeutics development efforts. Two different biological approaches, both predicated on vaccination, are discussed in this monograph as preclinical approaches for the treatment of AD and a TSE. Herein, I first describe an active vaccination approach that exploits immune shaping to engender a prophylactic T(H)2 response to Abeta in AD mouse models. Second, I describe a passive vaccination strategy whereby recombinant adeno-associated virus vectored delivery of anti-prion single-chain fragment variable antibodies attenuates disease progression and promotes life extension in a mouse TSE model.