A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice

Armine Hovakimyan,Anahit Ghochikyan,Irina Petrushina,Hayk Davtyan,William Carlen-Jones,Sepideh Kiani Shabestari,Karen Zagorski,Olga Svystun,Michael G Agadjanyan,Morgan A Coburn,Tatevik Antonyan,Gor Chailyan,David H Cribbs,Nikolai Petrovsky,Jean Paul Chadarevian

doi:10.1038/s41598-019-51809-2

Abstract

Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and therefore represents a promising target for immunotherapy. Targeting an appropriate B cell epitope in pathological tau could in theory produce an effective reduction of pathology without disrupting the function of normal native tau. Recent data demonstrate that the N-terminal region of tau (aa 2-18), termed the “phosphatase activation domain (PAD)”, is hidden within native Tau in a ‘paperclip’-like conformation. Conversely, PAD is exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and tau polymerization. Thus, we hypothesized that anti-tau2-18 antibodies may safely and specifically reduce pathological tau and prevent further aggregation, which in turn would neutralize tau toxicity. Therefore, we evaluated the immunogenicity and therapeutic efficacy of our MultiTEP platform-based vaccine targeting tau2-18 formulated with AdvaxCpG adjuvant (AV-1980R/A) in PS19 tau transgenic mice. The AV-1980R/A induced extremely high antibody responses and the resulting sera recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections. In addition, under non-denaturing conditions AV-1980R/A sera preferentially recognized AD-associated tau. Importantly, vaccination also prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy.

Highlights

Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and represents a promising target for immunotherapy
(Fig. 1a) formulated with AdvaxCpG adjuvant (AV-1980R/A, Fig. 1b) produced very high concentrations of antitau antibodies after just two immunizations (Fig. 2a)
The ratio of IgG1/ IgG2ab in all vaccinated mice was approximately 1, indirectly suggesting an equal contribution of both Th2 and Th1 cytokines to the immune response, which is consistent with the characteristics of AdvaxCpG 30

Summary

Introduction

Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and represents a promising target for immunotherapy. Vaccination prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy. Levels of Aβ oligomers correlate with disease severity[11,12,13,14], tau pathology more strongly correlates with the progression of AD9,15 Based on these data, we hypothesize that tau targeting immunotherapy should be applied either simultaneously with anti-Aβ therapy as a prophylactic measure or sequentially in the later stages of AD. Other studies have examined non-modified peptide-based adjuvanted vaccines, as well as antibodies specific to non-modified linear and conformational tau epitopes as potential anti-tau immunotherapies[24,25,26,27,28,29]

Methods

Results

Conclusion