Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical developmen

Conserving the holobiont

1. Organismal biology has undergone a dramatic paradigm shift in the last decade. The realization that host cells and genes are outnumbered by symbiotic microbial cells and their genes has forced us to rethink our focus on ‘individuals’. It is also becoming increasingly clear that the ecology and biology of animals and plants are intimately connected with their microbial partners. In the context of conserving functioning species, such revelatory insights beg the question—what exactly should we be trying to conserve? 2. Here, we review how an understanding of host–microbe interactions can benefit conservation biology. We propose a way forward for conservation biologists, to gather evidence of the potential effects of changes to plant and animal microbiomes, and to incorporate the holobiont concept into applied conservation practice. 3. In humans, microbes influence physiology, health, behaviour and psychology. In animals and plants, microbes similarly influence critically important components of health, communication and (in animals) behaviour. Together, the animal or plant and all of its associated micro-organisms are termed the holobiont. 4. At the same time, humans are now the strongest evolutionary force on the planet, causing global change at unprecedented scale. We know that microbial diversity in humans has been compromised in urban societies, with a growing list of consequences for health and function. While we still have limited evidence for similar effects in plants and animals, anthropogenic factors that affect diversity are also likely to affect animal and plant microbiomes, with similar associated effects on host function and health. 5. Microbiome research is still in its relative infancy, particularly in its application to plants and animals, yet the tools are becoming more widely available and affordable. Forward-looking conservation biologists could harness such tools and apply them to the study of plant and animal microbiomes with the goal of understanding which microbiota might be required to ensure future viability of conserved host populations. 6. For now, the precautionary principle applies. We suggest that, to meaningfully and effectively conserve a species, we must also consider how to conserve the bacteria, viruses, fungi and other symbionts intimately associated with that macro-organism

Coding of group odor in the subcaudal gland secreation of the European badger Meles meles: chemical composition and pouch microbiota

The fermentation hypothesis predicts that odor profiles of mammals depend partly on the primary gland products excreted by the animal and partly on the composition of the bacterial flora converting these into secondary metabolites. Some mammalian odors, such as shared group odors, however, need to be consistent yet flexible (e.g., to allow for changes in social-group affiliation), and are thus predisposed for microbial mediation. Using terminal restriction fragment (TRF) length polymorphism analyses we analyzed the microbial community in subcaudal-gland secretions of European badgers (Meles meles) in relation to the chemical scent profiles as determined by gas chromatography-mass spectrometry analyses (GCMS) of 66 adults belonging to six different social groups. We found a total of 50 TRFs and 125 different chemical compounds with a subset of four TRFs best explaining the structure in the chemical matrix. Nevertheless, although semiochemical profiles were group specific, microbial profiles were not. In our approach, however, the number of operational taxonomic units exceeded the numbers of TRFs, and thus our analyses were likely limited by the afforded resolution. As it is likely that the variation in metabolic activity is found at the species-, subspecies-, or even strain-level, future high-throughput sequencing can be expected to reveal more subtle differences in the microbial communities between social groups

Do Anogenital Gland Secretions of Giant Panda Code for Their Sexual Ability?

To test the hypothesis of whether anogenital gland secretions (AGS) of giant panda code for their sexual ability, we collected AGS samples of 11 male (5 adult and 6 subadult) and 14 female (7 adult and 7 subadult) captive giant pandas (Ailuropoda melanoleuca) from China Research and Conservation Center for the Giant Panda at Wolong, Sichuan, China from 1994 to 2002. The samples were analyzed by GC and GC-MS. The GC results showed that male and female pandas shared 20 constituents with equal capacity factors in the AGS. Further GC-MS analyses showed that there were a total of 95 compounds in the AGS. Nine constituents for the males and three for the females differed significantly in relative abundances between sexually active and inactive individuals, but no clear division between sexually active and inactive pandas by hierarchical cluster analyses on the relative abundances of a subset of 56 compounds. However, we were able to separate different age groups of male pandas by the constituents of AGS. 14 compounds were found significantly and negatively, and 8 compounds positively, correlated with pandas’ age by year. Our results suggest that the information contained in the AGS of panda might not code for pandas’ sexual ability but might for their age. These results will be valuable for captive breeding and conservation in the wild