Date Published: June 19, 2018
Publisher: BioMed Central
Author(s): 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.
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.
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.
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.
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.
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss , intracellular neurofibrillary tangles (NFTs) composed of microtubule-associated protein tau, and extracellular amyloid plaques formed by amyloid-β (Aβ) aggregates in the brain . Unlike Aβ plaques, the amount and extent of NFT pathology positively correlate with the severity of the cognitive deficit of AD [3, 4]. Tau inclusions are also found in other tauopathies that lack Aβ pathology, such as corticobasal degeneration, Pick’s disease, and progressive supranuclear palsy . Notably, mutations in the tau gene (such as P301S, P301L) cause some forms of frontotemporal dementia (FTD), indicating that tau dysfunction alone is sufficient to cause neurodegeneration . Current pharmacological treatment of AD is based on cholinesterase inhibitors and memantine. However, this treatment could not halt the disease’s progress .
Both hyperphosphorylated and truncated tau play a critical role in AD pathogenesis. Authors of many reports selectively targeted phosphorylated tau (phospho-tau) epitopes, including phospho-Ser396/phospho-Ser404 [32–34], phospho-Ser422 , or phospho-Thr231/phospho-Ser235 . However, most phosphoepitopes of tau such as phospho-Ser404 are present in healthy human brains , which raises concerns about the safety of immunotherapies targeting those phospho-tau species. Truncated tau is a pathogenic tau present in AD brains but not in normal human brains; thus, targeting truncated tau may be a more promising approach . In this study, we chose tau294–305 as our targeting epitope because it is a structural determinant of the truncated tau protein for the pathological tau-tau interaction. This epitope contains a motif, “HXPGGG,” that localizes not only in tau299–304 (within MTBR2) but also in tau268–273 (within MTBR1), tau330–335 (within MTBR3), and tau362–367 (within MTBR4) [17, 38]. Therefore, the antibodies induced by tau294–305 may simultaneously bind to MTBR1–4.
In summary, our study indicates that the HBc VLP-based T294-HBc vaccine exerted favorable effects on cognition and neuropathology in the Tau.P301S transgenic mouse model by inducing high titers of antibodies against truncated tau; decreasing the levels of truncated tau monomer, oligomer, and hyperphosphorylated tau; increasing synaptophysin levels; and suppressing microgliosis and astrogliosis in mouse brains. Moreover, T294-HBc VLP-induced antibodies could simultaneously bind to MTBR 1–4 [tau263–274, tau294–305, tau325–336, tau357–368, and tau294–305(P301S)], indicating that this vaccine has promising therapeutic potential for the treatment of FTD and AD.