Hepatitis B core VLP-based mis-disordered tau vaccine elicits strong immune response and alleviates cognitive deficits and neuropathology progression in Tau.P301S mouse model of Alzheimer's disease and frontotemporal dementia.

Abstract

BACKGROUND:

Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau294-305, an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau294-305-targeted approach may have beneficial effects in the treatment of AD and FTD.

METHODS:

In this study, we genetically fused tau294-305 epitope to the hepatitis B virus core protein (HBc) major immunodominant region (MIR) (with the resultant protein termed T294-HBc), and we subcutaneously immunized a Tau.P301S transgenic mouse model of FTD and AD with T294-HBc four times. The levels and characteristics of antibodies induced by T294-HBc were determined by enzyme-linked immunosorbent assay. The effect of T294-HBc on the cognitive deficits of Tau.P301S mice was tested using the Morris water maze test, novel object recognition, and a Y-maze test. Western blot analysis and IHC were applied to measure the effect of T294-HBc on tau pathologies and neuroinflammation in the mouse brains.

RESULTS:

The results showed that T294-HBc self-assembled into HBc chimeric virus-like particles (VLPs) with tau294-305 displayed on the surface and that it induced high antibody titers specifically against the mis-disordered truncated tau. Further investigation showed that these antibodies simultaneously bound to microtubule-binding regions 1-4 (MTBR1-4) [tau263-274, tau294-305, tau325-336, tau357-368 and tau294-305(P301S)]. Moreover, T294-HBc VLP vaccination significantly ameliorated memory and cognitive decline; reduced the levels of AT8-positive tau, truncated tau monomer, and oligomer; attenuated microgliosis and astrogliosis; and rescued synaptic deficits in Tau.P301S transgenic mice.

CONCLUSIONS:

T294-HBc VLP vaccine elicited strong immune response and alleviated cognitive deficits and neuropathology progression in Tau.P301S mice, indicating that the T294-HBc VLP vaccine has promising therapeutic potential for the treatment of AD and FTD.

• Authors: Mei Ji, Xi-Xiu Xie, Dong-Qun Liu, Xiao-Lin Yu, Yue Zhang, Ling-Xiao Zhang, Shao-Wei Wang, Ya-Ru Huang, Rui-Tian Liu
• Journal: Alzheimer's research & therapy (Alzheimers Res Ther) Vol. 10 Issue 1 Pg. 55 (06 19 2018) ISSN: 1758-9193 [Electronic] England
• PMID: 29914543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hepatitis B Vaccines
• Immunodominant Epitopes
• Nerve Tissue Proteins
• Vaccines, Virus-Like Particle
• tau Proteins
• Serine
• Proline

Topics

• Alzheimer Disease (complications, genetics)
• Animals
• Cognition Disorders (etiology, therapy)
• Disease Models, Animal
• Dose-Response Relationship, Immunologic
• Exploratory Behavior
• Female
• Frontotemporal Dementia (complications, genetics)
• Hepatitis B Vaccines (chemistry, metabolism)
• Immunization (methods)
• Immunodominant Epitopes (therapeutic use)
• Male
• Maze Learning
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation (genetics)
• Nerve Tissue Proteins (metabolism)
• Proline (genetics)
• Recognition, Psychology
• Serine (genetics)
• Treatment Outcome
• Vaccines, Virus-Like Particle (therapeutic use)
• tau Proteins (genetics, immunology, metabolism)