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

Alzheimers Res Ther. 2018 Jun 19;10(1):55. doi: 10.1186/s13195-018-0378-7.

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.

Keywords: Alzheimer’s disease; Frontotemporal dementia; Hepatitis B core protein; Neurofibrillary tangles; Truncated tau; Vaccine; Virus-like particles (VLPs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Animals
  • Cognition Disorders / etiology*
  • Cognition Disorders / therapy*
  • Disease Models, Animal
  • Dose-Response Relationship, Immunologic
  • Exploratory Behavior
  • Female
  • Frontotemporal Dementia / complications*
  • Frontotemporal Dementia / genetics
  • Hepatitis B Vaccines / chemistry
  • Hepatitis B Vaccines / 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
  • tau Proteins / immunology*
  • tau Proteins / metabolism

Substances

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