Abstract
Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer’s disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.
Highlights
Pathological species of microtubule-associated protein tau (MAPT)[1] accumulate in the brain of Alzheimer’s disease (AD) and diverse non-AD neurodegenerative disorders collectively referred to as tauopathies, including frontotemporal lobar degeneration (FTLD) characterized by tau deposition (FTLD-tau)[2]
It has been documented that mutant tau proteins provoke the generation of misfolded tau, leading to the deposition of tau fibrils and tau-induced neurotoxicity in FTDP-17 patients and transgenic mouse models[30,31] and giving a rationale for immunotherapeutically targeting pathological tau by vaccination
We developed a nasal anti-tau vaccination using a Sendai virus (SeV) vector carrying a secreted form of human tau with P301S mutation as an immunogen
Summary
Pathological species of microtubule-associated protein tau (MAPT)[1] accumulate in the brain of Alzheimer’s disease (AD) and diverse non-AD neurodegenerative disorders collectively referred to as tauopathies, including frontotemporal lobar degeneration (FTLD) characterized by tau deposition (FTLD-tau)[2]. Tau is released from neurons into extracellular space[6,7], raising the importance of clearing extracellular tau by immunotherapy including anti-tau vaccination, which has emerged as a promising approach to tauopathies[8,9]. Accumulated evidence in basic research supports the idea that immunotherapy against tau may be a promising therapeutic approach for tauopathy. We developed nasal tau vaccination using Sendai virus (SeV) vector. The replication and transcription of our SeV vector occur and continue for about a month after administration in the cytoplasm of epithelial cells in the respiratory system[21,22], and its gene never integrates into the host DNA23. In the brainstem of FTLD-tau mice at 24 weeks after tau-v injection, but the difference in PET signals between the treatment
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