Abstract
BackgroundTruncated 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.MethodsIn 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.ResultsThe 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.ConclusionsT294-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.
Highlights
Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD)
The preparation of T294-hepatitis B virus core protein (HBc) To improve the immunogenicity of tau294–305, we fused it to the HBc major immunodominant region (MIR) region
T294-HBc Virus-like particles (VLPs) effectively elicit high-titer antibodies against mis-disordered tau (151–391/2N4R) Tau.P301S transgenic mice were immunized subcutaneously with 100 μg of T294-HBc VLPs for four times, and the serum antibody titer was detected by enzyme-linked immunosorbent assay (ELISA) (Fig. 2a)
Summary
We genetically fused tau294305 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. Plasmid construction and protein expression A truncated HBc gene (coding for amino acids 1 to 149) was cloned into pBR327 vector, which was a kind gift from Professor Andris Kazaks (Latvian Biomedical Research and Study Center, Latvia) [23]. The sample prepared by ammonium sulfate precipitation was subjected to sucrose discontinuous gradient centrifugation at 112,000 × g for 16 hours at 4 °C. Purified protein was concentrated and determined by using a bicinchoninic acid protein assay kit (Pierce, Rockford, IL, USA). Full-length tau isoform 2N4R construct was gifted by Professor Virginia M.-Y. Mis-disordered tau (151–391/2N4R) and full-length tau isoform 2N4R were prepared with E. coli BL21 (DE3) as described previously, with some modifications [26, 27]
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