# Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy

## TL;DR

A vaccine targeting a specific phosphorylated tau site (PHF1) was more effective than another in reducing brain pathology and improving memory in a mouse model of tau-related dementia.

## Contribution

A novel VLP-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) was shown to be more effective than one targeting Ser199/Ser202 (AT8) in reducing tau pathology and cognitive deficits.

## Key findings

- Qβ-PHF1 vaccine rescued cognitive deficits and reduced pathological tau and microgliosis in a mouse model of tauopathy.
- Antibodies from Qβ-PHF1 vaccinated mice reacted to tau pathology in human Alzheimer's brain tissue.
- Both Qβ-AT8 and Qβ-PHF1 vaccines induced high-titer antibody responses against their respective pTau epitopes.

## Abstract

Tauopathies, including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.