Dataset Information

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.

ABSTRACT: We have identified structural determinants on tau protein that are essential for pathological tau-tau interaction in Alzheimer's disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8, represent a novel target for tau-directed therapy. In order to validate this target, we have developed an active vaccine, AADvac1.A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting structural determinants on mis-disordered tau protein that are essential for pathological tau-tau interaction. The efficacy of the vaccine was tested in a transgenic rat model of human tauopathies. Toxicology and safety pharmacology studies were conducted under good laboratory practice conditions in multiple rodent and nonrodent species.We have administered the tau peptide vaccine to a rat model of AD to investigate whether the vaccine can improve its clinical, histopathological and biochemical AD phenotype. Our results show that vaccination induced a robust protective humoral immune response, with antibodies discriminating between pathological and physiological tau. Active immunotherapy reduced the levels of tau oligomers and the extent of neurofibrillary pathology in the brains of transgenic rats. Strikingly, immunotherapy has reduced AD-type hyperphosphorylation of tau by approximately 95%. Also, the tau peptide vaccine improved the clinical phenotype of transgenic animals. Toxicology and safety pharmacology studies showed an excellent safety and tolerability profile of the AADvac1 vaccine.Active immunisation targeting crucial domains of Alzheimer tau eliminated tau aggregation and neurofibrillary pathology. Most importantly, the AD type of tau hyperphosphorylation was abolished by vaccination across a wide range of AD phospho-epitopes. Our results demonstrate that active immunisation led to elimination of all major hallmarks of neurofibrillary pathology, which was reflected by a profound improvement in the clinical presentation of transgenic rats. This makes the investigated tau peptide vaccine a highly promising candidate therapeutic for the disease-modifying treatment of AD. The tested vaccine displayed a highly favourable safety profile in preclinical toxicity studies, which opens up the possibility of using it for AD prophylaxis in the future. The vaccine has already entered phase I clinical trial under the name AADvac1.Current Controlled Trials NCT01850238. Registered 7 May 2013.

SUBMITTER: Kontsekova E

PROVIDER: S-EPMC4255368 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Kontsekova Eva E Zilka Norbert N Kovacech Branislav B Novak Petr P Novak Michal M

Alzheimer's research & therapy 20140801 4

<h4>Introduction</h4>We have identified structural determinants on tau protein that are essential for pathological tau-tau interaction in Alzheimer's disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8, represent a novel target for tau-directed therapy. In order to validate this target, we have developed an active vaccine, AADvac1.<h4>Methods</h4>A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting stru ...[more]

PMID: 25478017

Similar Datasets

Project description:IntroductionPathologically modified tau protein is the main feature of Alzheimer's disease (AD) and related tauopathies. Therefore, immunotherapies that target mis-disordered tau represent a promising avenue for the disease-modifying treatment of AD. In this report, we present our discovery of (1) a novel target for tau immunotherapy; (2) monoclonal antibody DC8E8, which neutralizes this target; and (3) the results of efficacy studies of DC8E8 in a murine model of tauopathy.MethodsIn vitro tau oligomerisation assays were used for the selection of antibodies. The therapeutic efficacy of DC8E8 was evaluated in transgenic mice. The structure of the DC8E8 epitope was determined by X-ray crystallography.ResultsScreening of a panel of monoclonal antibodies for their inhibitory activity in an in vitro pathological tau-tau interaction assay yielded DC8E8, which reduced the amount of oligomeric tau by 84%. DC8E8 recognised all developmental stages of tau pathology in AD human brains, including pretangles and intra- and extracellular tangles. Treatment with DC8E8 in a mouse AD model expressing mis-disordered human tau significantly reduced the amount of insoluble oligomerised tau and the number of early and mature neurofibrillary tangles in the transgenic mouse brains. By using a panel of tau-derived peptides in a competitive enzyme-linked immunosorbent assay, we identified the tau domain essential for pathological tau-tau interaction, which is targeted by DC8E8. The antibody was capable of binding to four highly homologous and yet independent binding regions on tau, each of which is a separate epitope. The X-ray structure of the DC8E8 Fab apo form, solved at 3.0 Å, suggested that the four DC8E8 epitopes form protruding structures on the tau molecule. Finally, by kinetic measurements with surface plasmon resonance, we determined that antibody DC8E8 is highly discriminatory between pathological and physiological tau.ConclusionsWe have discovered defined determinants on mis-disordered truncated tau protein which are responsible for tau oligomerisation leading to neurofibrillary degeneration. Antibody DC8E8 reactive with these determinants is able to inhibit tau-tau interaction in vitro and in vivo. DC8E8 is able to discriminate between the healthy and diseased tau proteome, making its epitopes suitable targets, and DC8E8 a suitable candidate molecule, for AD immunotherapy.

Project description:Granulovacuolar degeneration (GVD) is a common feature in Alzheimer's disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC-MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets