S4‐04‐08: Immunotherapy Targeting Pathologically Phosphorylated Tau in a Tauopathy Mouse Model

Abstract

It has now become clear that amyloid immunization, while displaying clearance of amyloid, not only caused neuroinflammation, but did not improve cognitive impairment (and did not reduce the neurofibrillary-tangles (NFTs)). As NFTs are the best correlate with dementia, targeting the NFT pathology seems to be a preferential goal. As an aggregated protein, tau in the NFTs - seems to be a candidate for immunotherapy. Yet, the encephalitogenicity of full-length tau recently reported by us (Arch Neurol, 2006) demands to selectively target pathological tau and address both, efficacy and safety. Here we set up to specifically target pathologically phosphorylated (P)-tau conformers by immunizing NFT-mice with NFT-related P-tau peptides, using an immunization protocol aimed to predispose a proinflammatory milieu in CNS, similarly to what we used when the neurotoxicity of tau protein was detected (i.e., the use of complete-Freund’s-adjuvant (CFA) with pertussis-toxin (PT)). We immunized NFT-mice with a mixture of three tau-peptides phosphorylated at five residues characteristic of NFT-pathology with CFA and PT. Clinical, immunological and pathological evaluations were performed. Anti-P-tau Abs were detected in sera of tau-immunized mice. However, no neurological deficits were noted following P-tau-immunotherapy for at least 8 months. Reduced NFT-burden (∼40%; p < 0.001) was noticed in the brains and spinal cords of immunized animals relative to controls, as indicated by Gallyas-staining and with AT8- and AT180-immunohistochemistry This was accompanied with an increase (∼20%; p = 0.01) in microglial burden as indicated by lectin staining. Our results show: 1. A decreased NFT-burden following P-tau-immunotherapy. This is in accord with Asuni et al. (2007) who used a similar approach of immunizing mice against NFTs, yet with a different P-tau immunogene and immunization protocol (without CFA + PT). 2. Presence of anti-P-tau Abs in the sera of immunized mice with no evidence of clinical deficits, indicating that these specific P-peptide-immunogens used by us are not encephalitogenic, in contrast to the encephalitogenicity of full-length tau, demonstrated by us previously. This anti-NFT effect induced by immunotherapy targeting pathologically phosphorylated tau, together with the lack of encephalitogenicity of these P-peptide-immunogens, points to the therapeutic anti-NFT potential of P-tau-immunotherapy.