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.

Hulse, J. P.; Maphis, N. M.; Peabody, J.; Chackerian, B.; Bhaskar, K.

doi:10.1101/2024.04.05.588338

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bioRxiv · 10.1101/2024.04.05.588338

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.

Hulse, J. P.·Maphis, N. M.·Peabody, J.·Chackerian, B.·Bhaskar, K.

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Abstract

Tauopathies, including Alzheimers 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 (Q{beta}-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Q{beta} 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 Q{beta} VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Q{beta}-AT8) and Ser396/Ser404 (Q{beta}-PHF1). Both Q{beta}-AT8 and Q{beta}-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Q{beta}-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Q{beta}-AT8 and Q{beta}-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.

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Hulse, J. P., Maphis, N. M., Peabody, J., Chackerian, B., Bhaskar, K.. 2024-04-09. 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.. https://doi.org/10.1101/2024.04.05.588338

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