Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer's disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2 Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS, compared to those who have familial AD caused by triplication of APP Significance Statement:Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease, which has been previously attributed to people with Down syndrome having three copies of the APP gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al. 2018, Brain; Tosh et al. 2021 Scientific Reports). Here, we use a mapping approach to narrow-down the genetic cause of the modulation of pathology; demonstrating that gene(s) on chromosome 21 decrease amyloid-β accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this

Urbanisation, climate change and health equity: how can health promotion contribute?

We live in a world that is constantly changing and is challenging established approaches to managing human and ecological health. Two key drivers of change are urbanisation and global climate change. This commentary is concerned with the interrelationship of these drivers with human and ecological health, proposing that health promotion practitioners need to actively seek a new role in the process of creating urban environments that support social and ecological well-being. It provides practitioners with an up-to-date synthesis of climate change science and future projections, the literature around the health impacts of climate change and potential health challenges to urban communities. We argue that health promotion cannot respond to the challenges created by climate change and urbanisation, nor can it meet its own mandate without shifting from an anthropogenic-focussed approach toward embracing a multi-scale, collaborative approach outside the health sector. We suggest that the underlying principles of health promotion, which include equity and community engagement at all scales, are critical to the evolution of thriving urban environments. Food security is given as an example to demonstrate the proposed shift away from an anthropogenic and urban focus toward a socio-ecological approach (i.e. resilience thinking) that provides a framework for collaboration between sectors working with unpredictable global systems. In so doing, the commentary provides practitioners with guidance on the complex science of climate change and its impact on health in urban settings, as well as highlighting the skills that they can bring to creating resilient urban settlements in these times of change

Planetary health pedagogy: Preparing health promoters for 21st-century environmental challenges

Issue addressed: Multiple interconnected drivers threaten the health and wellbeing of humans and the environment, including biodiversity loss, climate change, pollution, rapid urbanisation and displacement. This requires enhanced literacy on health of the environment and innovation in problem conceptualisation and cross-sectoral solutions. Contemporary mandates (eg, Ottawa Charter) task health promoters to tackle the human and environmental health crisis. To address the complex determinants across multiple settings, health promotion graduates require competencies in interdisciplinary collaboration grounded in systems thinking. They also require knowledge and agility to leverage multiple gains from health promotion action that benefits people and planet. Similarly, health promotion practitioners are currently aware of the need for skills to deliver co-benefits to people and planet. Planetary health, as theory and framework, provides a socio-ecological focus, systems thinking approach, co-benefits framework for action and foundational basis to enhance health promotion graduates' skills and competencies to address multiple health and planetary challenges. To date, there have been limited practical attempts to address these challenges. Method: A desktop review and synthesis of teaching and learning scholarship in planetary health were coupled with iterative critical reflections of teaching practice, and the use of two case studies, to illuminate innovations in health promotion competencies. Results: Two examples of how planetary health promotion challenges are addressed through teaching and learning scholarship are presented to illustrate the use of a tailored sustainability tool and a deliberative interdisciplinary approach to collaboration, delivered within a course that constructively aligns curriculum content and assessment. Conclusion: A bespoke model, the Sustainability Wheel of Fortune, combined with constructive interactive teaching approaches, adds interdisciplinary collaboration and systems thinking approaches to the knowledge and practice of planetary health. A postgraduate microcredential fast-tracks knowledge and skills acquisition for recent graduates and established practitioners interested in upskilling for planning planet and population health co-benefits. So what?: The Sustainability Wheel of Fortune provides health promotion students with a model for understanding, and addressing, complex global and local challenges. The microcredential builds on health promotion competencies to develop interdisciplinary and systems-based approaches to planetary health challenges

Plant responses to grazing: A global synthesis.

Herbivory by domestic and wild ungulates is a major driver of global vegetation dynamics. However, grazing is not considered in dynamic global vegetation models, or more generally in studies of the effects of environmental change on ecosystems at regional to global scale. An obstacle to this is a lack of empirical tests of several hypotheses linking plant traits with grazing. We, therefore, set out to test whether some widely recognized trait responses to grazing are consistent at the global level. We conducted a meta-analysis of plant trait responses to grazing, based on 197 studies from all major regions of the world, and using six major conceptual models of trait response to grazing as a framework. Data were available for seven plant traits: life history, canopy height, habit, architecture, growth form (forb, graminoid, herbaceous legume, woody), palatability, and geographic origin. Covariates were precipitation and evolutionary history of herbivory. Overall, grazing favoured annual over perennial plants, short plants over tall plants, prostrate over erect plants, and stoloniferous and rosette architecture over tussock architecture. There was no consistent effect of grazing on growth form. Some response patterns were modified by particular combinations of precipitation and history of herbivory. Climatic and historical contexts are therefore essential for understanding plant trait responses to grazing. Our study identifies some key traits to be incorporated into plant functional classifications for the explicit consideration of grazing into global vegetation models used in global change research. Importantly, our results suggest that plant functional type classifications and response rules need to be specific to regions with different climate and herbivory history.Fil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Lavorel, Sandra. Universite Joseph Fourier; FranciaFil: McIntayre, Sue. CSIRO Sustainable Ecosystems; Nueva ZelandaFil: Falczuk, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Casanoves, Fernando. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias; ArgentinaFil: Milchunas, Daniel G.. CSIRO Sustainable Ecosystems; Nueva Zelanda. State University of Colorado - Fort Collins; Estados UnidosFil: Skarpe, Christina. Norwegian Institute for Nature Research; NoruegaFil: Rusch, Graciela. Norwegian Institute for Nature Research; NoruegaFil: Sternberg, Marcelo. CSIRO Sustainable Ecosystems; Nueva Zelanda. Tel Aviv University; IsraelFil: Noy-meir, Imanuel. The Hebrew University of Jerusalem; IsraelFil: Landsberg, Jill. CSIRO Sustainable Ecosystems; Nueva ZelandaFil: Zhang, Wei. University of British Columbia; CanadáFil: Clark, Harry. Grasslands Research Centre; Nueva ZelandaFil: Campbell, Bruce D.. Hort Research Mt Albert; Nueva Zeland

Trisomy of human chromosome 21 enhances amyloid-beta deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.status: publishe