Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer’s Disease Like Tau Aggregation

Abstract

Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer’s disease (AD) specific B cell epitopes with foreign (bacterial) T cell epitopes induced fast immune responses with high IgG1 titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

A walk through tau therapeutic strategies

“…Like their passive immunotherapy counterparts, active vaccines targeting the mid-region, microtubule binding domain and C-terminus have been extensively investigated in preclinical studies (Table 2). Most of these studies demonstrated reduction in tau pathology [14, 30, 167, 270, 274, 322] along with improvement in cognitive or sensorimotor abilities in animals [36, 37, 167, 322, 326] (Table 3).…”

“…Many preclinical studies of the tau vaccines have analysed the antibody response in a rather descriptive manner as “good, robust, high or low”, and did not elaborate on its quantitative aspect [14, 37, 270, 322]. Only two studies published so far, have defined the titer of the antibody response [167, 274]. There is an urgent need for development of common standards for the measurement of antibody response with the most sensitive and reproducible methods.…”

Cognizance of posttranslational modifications in vaccines: A way to enhanced immunogenicity

“…In Alzheimer's disease, phosphorylation plays a very notable role in the development of vaccine designing. Richter et al ( 2014 ), in the Year 2014, reported a doubly phosphorylated tau neuropeptide vaccine against Alzheimer's disease. They have designed this peptide vaccine by utilizing the B cell neoepitopes from the tau protein (at phosphorylated sites‐ Tau 199–208 [pS202/pT205], Tau 209–217 [pT212/pS214], and Tau 229–237 [pT231/pS235]) and fused these epitopes with the Clostridium tetani (tetanus) toxin or the Ag85B antigen from Mtb and transgenic mice P301S was immunized with these doubly phosphorylated peptides.…”

Sexual dimorphism in behavior, neuropathology, and biomarkers in a tau P301S mouse model of Alzheimer’s disease

“…Given that typical amyotrophy and dyskinesia occur in P301S Tg mice, grip strength test, accelerating rotarod test, and stride length test are widely used methods to evaluate the efficiency of tautargeting AD drugs in tau Tg mice [27,32,40,41]. Nevertheless, the impact of sex differences on these tests remains unknown.…”