Background: Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau(294-305), an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau(294-305)-targeted approach may have beneficial effects in the treatment of AD and FTD. Methods: In this study, we genetically fused tau(294-305) 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) [tau(263-274), tau(294-305,) tau(325-336,) tau(357-368) and tau(294-305)(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.