Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Alzheimer's Research & Therapy | Issue 1/2018

Login to get access

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.
Literature
1.
2.
3.
4.
5.
Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol. 1999;9(4):663–79.CrossRefPubMed
6.
Bugiani O, et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999;58(6):667–77.CrossRefPubMed
7.
Godyn J, et al. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep. 2016;68(1):127–38.CrossRefPubMed
8.
Kovacech B, Skrabana R, Novak M. Transition of tau protein from disordered to misordered in Alzheimer’s disease. Neurodegener Dis. 2010;7(1–3):24–7.CrossRefPubMed
9.
Zilka N, et al. Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006;580(15):3582–8.CrossRefPubMed
10.
11.
Panza F, et al. Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy. 2016;8(9):1119–34.CrossRefPubMed
12.
Novak P, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–34.CrossRefPubMed
13.
Sterner RM, Takahashi PY, Yu Ballard AC. Active vaccines for Alzheimer disease treatment. J Am Med Dir Assoc. 2016;17(9):862.e11–5.CrossRef
14.
15.
Robinson SR, et al. Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging. 2004;25(5):609–15.CrossRefPubMed
16.
Pride M, et al. Progress in the Active Immunotherapeutic Approach to Alzheimer’s Disease: Clinical Investigations into AN1792-Associated Meningoencephalitis. Neurodegener Dis. 2008;5(3-4):194–6.CrossRefPubMed
17.
Kontsekova E, et al. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther. 2014;6(4):44.CrossRefPubMedPubMedCentral
18.
Wiessner C, et al. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci. 2011;31(25):9323–31.CrossRefPubMed
19.
Roldao A, et al. Virus-like particles in vaccine development. Expert Rev Vaccines. 2010;9(10):1149–76.CrossRefPubMed
20.
Pumpens P, Grens E. HBV core particles as a carrier for B cell/T cell epitopes. Intervirology. 2001;44(2–3):98–114.CrossRefPubMed
21.
Pumpens P, Grens E. Artificial genes for chimeric virus-like particles. In: Khudyakov YE, Fields HA, editors. Artificial DNA: methods and applications. Boca Raton: CRC Press; 2002. p. 249–327.
22.
Pumpens P, et al. Construction of novel vaccines on the basis of the virus-like particles: hepatitis B virus proteins as vaccine carriers. In: Khudyakov YE, editor. Medicinal protein engineering. Boca Raton: CRC Press; 2009. p. 205–48.
23.
Kazaks A, et al. Melanoma vaccine candidates from chimeric hepatitis B core virus-like particles carrying a tumor-associated MAGE-3 epitope. Biotechnol J. 2008;3(11):1429–36.CrossRefPubMed
24.
Sominskaya I, et al. A VLP library of C-terminally truncated Hepatitis B core proteins: correlation of RNA encapsidation with a Th1/Th2 switch in the immune responses of mice. PLoS One. 2013;8(9):e75938.CrossRefPubMedPubMedCentral
25.
Birkett A, et al. A modified hepatitis B virus core particle containing multiple epitopes of the Plasmodium falciparum circumsporozoite protein provides a highly immunogenic malaria vaccine in preclinical analyses in rodent and primate hosts. Infect Immun. 2002;70(12):6860–70.CrossRefPubMedPubMedCentral
26.
Li W, Lee VM. Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry. 2006;45(51):15692–701.CrossRefPubMed
27.
Csokova N, et al. Rapid purification of truncated tau proteins: model approach to purification of functionally active fragments of disordered proteins, implication for neurodegenerative diseases. Protein Expr Purif. 2004;35(2):366–72.CrossRefPubMed
28.
29.
Iba M, et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci. 2013;33(3):1024–37.CrossRefPubMedPubMedCentral
30.
Kovac A, et al. Misfolded truncated protein tau induces innate immune response via MAPK pathway. J Immunol. 2011;187(5):2732–9.CrossRefPubMed
31.
Yoshiyama Y, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53(3):337–51.CrossRefPubMed
32.
Asuni AA, et al. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007;27(34):9115–29.CrossRefPubMed
33.
Bi M, et al. Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS One. 2011;6(12):e26860.CrossRefPubMedPubMedCentral
34.
Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci. 2010;30(49):16559–66.CrossRefPubMedPubMedCentral
35.
Troquier L, et al. Targeting phospho-Ser422 by active tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res. 2012;9(4):397–405.CrossRefPubMedPubMedCentral
36.
Richter M, Hoffmann R, Singer D. T-cell epitope-dependent immune response in inbred (C57BL/6J, SJL/J, and C3H/HeN) and transgenic P301S and Tg2576 mice. J Pept Sci. 2013;19(7):441–51.CrossRefPubMed
37.
Hanger DP, et al. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem. 2007;282(32):23645–54.CrossRefPubMed
38.
Kontsekova E, et al. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther. 2014;6(4):45.CrossRefPubMedPubMedCentral
39.
40.
41.
Chai X, et al. Passive immunization with anti-tau antibodies in two transgenic models reduction of tau pathology and delay of disease progression. J Biol Chem. 2011;286(39):34457–67.CrossRefPubMedPubMedCentral
42.
Yanamandra K, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80(2):402–14.CrossRefPubMedPubMedCentral
43.
Banks WA. Immunotherapy and neuroimmunology in Alzheimer’s disease: a perspective from the blood-brain barrier. Immunotherapy. 2010;2(1):1–3.CrossRefPubMed
44.
Lee SH, et al. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement. Cell Rep. 2016;16(6):1690–700.CrossRefPubMed
45.
Metadata
Title
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
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
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2018
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-018-0378-7

Other articles of this Issue 1/2018

Alzheimer's Research & Therapy 1/2018 Go to the issue

Debate

Heterogeneity of Alzheimer’s disease: consequence for drug trials?

Research

Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study

Research

Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology

Research

Alzheimer’s disease master regulators analysis: search for potential molecular targets and drug repositioning candidates

Research

Discovery and validation of autosomal dominant Alzheimer’s disease mutations

Research

A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation