Different Amyloid-β Self-Assemblies Have Distinct Effects on Intracellular Tau Aggregation.

Alzheimer's disease (AD) pathology is characterized by the aggregation of beta-amyloid (Aβ) and tau in the form of amyloid plaques and neurofibrillary tangles in the brain. It has been found that a synergistic relationship between these two proteins may contribute to their roles in disease progression. However, how Aβ and tau interact has not been fully characterized. Here, we analyze how tau seeding or aggregation is influenced by different Aβ self-assemblies (fibrils and oligomers). Our cellular assays utilizing tau biosensor cells show that transduction of Aβ oligomers into the cells greatly enhances seeded tau aggregation in a concentration-dependent manner. In contrast, transduced Aβ fibrils slightly reduce tau seeding while untransduced Aβ fibrils promote it. We also observe that the transduction of α-synuclein fibrils, another amyloid protein, has no effect on tau seeding. The enhancement of tau seeding by Aβ oligomers was confirmed using tau fibril seeds derived from both recombinant tau and PS19 mouse brain extracts containing human tau. Our findings highlight the importance of considering the specific form and cellular location of Aβ self-assembly when studying the relationship between Aβ and tau in future AD therapeutic development

The Australian Farm Business Management Network: Industry, Education, Consultancy and Research Coming Together

Under the sponsorship of the University of Sydney, on 5-6th December 2002 the future of farm management in Australia was discussed. The fundamental conclusion achieved by key primary industry representatives, corporate executives, academics, consultants and researchers is that farm management will have a more significant role to play in the future than previously in servicing the primary sector. The idea of farm management as a profession was proposed. Its basis would be business management supported by farming systems and technology, and using an holistic approach to action (i.e. finance, people and environment). The new profession of Farm Business Management would seek to influence education, research, consultancy and extension in Australia. Interested parties participating of the 2002 National Farm Management Workshop came away with the idea of championing a consultative network, constituted by interested institutions and interested individuals, as a first step in the process of nurturing the future development of farm business management. By integrating farmers and academics with corporate executives, consultants and researchers the objective is to behave as a consultative group. This group will influence educational models, implement consultancy and research strategies, and network in social and professional terms. Moreover, this network will provide a systematic opportunity for the channelling of farm business management and farming systems related information at different levels for education, extension and scientific purposes. This network is called the Australian Farm Business Management Network (AFBMnetwork).Institutional and Behavioral Economics,

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel.

α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs

Galaxy Zoo: Disentangling the Environmental Dependence of Morphology and Colour

We analyze the environmental dependence of galaxy morphology and colour with two-point clustering statistics, using data from the Galaxy Zoo, the largest sample of visually classified morphologies yet compiled, extracted from the Sloan Digital Sky Survey. We present two-point correlation functions of spiral and early-type galaxies, and we quantify the correlation between morphology and environment with marked correlation functions. These yield clear and precise environmental trends across a wide range of scales, analogous to similar measurements with galaxy colours, indicating that the Galaxy Zoo classifications themselves are very precise. We measure morphology marked correlation functions at fixed colour and find that they are relatively weak, with the only residual correlation being that of red galaxies at small scales, indicating a morphology gradient within haloes for red galaxies. At fixed morphology, we find that the environmental dependence of colour remains strong, and these correlations remain for fixed morphology \textit{and} luminosity. An implication of this is that much of the morphology--density relation is due to the relation between colour and density. Our results also have implications for galaxy evolution: the morphological transformation of galaxies is usually accompanied by a colour transformation, but not necessarily vice versa. A spiral galaxy may move onto the red sequence of the colour-magnitude diagram without quickly becoming an early-type. We analyze the significant population of red spiral galaxies, and present evidence that they tend to be located in moderately dense environments and are often satellite galaxies in the outskirts of haloes. Finally, we combine our results to argue that central and satellite galaxies tend to follow different evolutionary paths.Comment: 19 pages, 18 figures. Accepted for publication in MNRA

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease