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Alzheimer’s disease (AD) is characterized by the accumulation of tau tangles and amyloid-β plaques in the brain with accompanied neurodegeneration. Phosphorylation of tau at specific sites occurs early in the disease process and has been shown to drive tau pathology which correlates with disease progression. Promoting the clearance of pathological tau may be a useful therapeutic strategy. Previously, we developed Qβ bacteriophage virus-like particle (VLP) vaccines displaying phosphorylated Thr181 tau peptides that promoted robust immune response, tau clearance, and improved memory. Here we report characterization and comparison of a Qβ-PHF-1-VLP and a Qβ-AT8-VLP vaccine. Transgenic rTg4510 mice were administered three bi-weekly intramuscular injections of Qβ control or Qβ conjugated to peptides corresponding to the tau PHF-1 site or the tau AT8 site. Serum antibody titers were assessed using ELISA. Cognitive function was assessed using Morris Water Maze (MWM) and Novel Object Recognition (NOR) tasks. Western blot and immunohistochemical analyses were performed to assess the levels of phosphorylated and aggregated tau. Both Qβ-PHF-1 and Qβ-AT8 vaccination induced a robust antibody response compared to Qβ control. Qβ-PHF-1 significantly reduced phosphorylated and Sarkosyl-insoluble tau in the brain compared to Qβ control while Qβ-AT8 did not. Qβ-PHF-1 vaccination ameliorated delay-dependent memory deficits assessed by NOR but did not rescue spatial memory deficits assessed by MWM (unlike Qβ-pT181 which also rescues spatial memory-PMID: 31428463). Qβ-AT8 failed to rescue any deficits in delay-dependent or spatial memory. Qβ-PHF-1 also reduces inflammatory microgliosis observed by immunohistochemistry compared to Qβ control. In summary, Qβ-PHF-1 vaccine outperforms the Qβ-AT8 vaccine, but both are less efficacious than Qβ-pT181.


NIH/NINDS R01NS083704, RF1NS083704-05A1, UNM HSC Research Allocation Committee Pilot Grant.

Poster presented at the Brain & Behavioral Health Research Day 2023

1st Place Poster prize for Basic Science.



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