Genetic Mapping of APP and Amyloid-ß 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 buildup of aggregated amyloid-ß (Aß) and tau proteins in the brain. Aß is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aß accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aß 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 Aß accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aß 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/Aß 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 in DS, compared with 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 (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (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; Tosh et al., 2021). 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 Aß 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.

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.

Trisomy of human chromosome 21 enhances amyloid-ß 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-ß aggregation, deposition of amyloid-ß 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-ß aggregation correlates with an unexpected shift in soluble amyloid-ß 40/42 ratio. This alteration in amyloid-ß 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-ß. 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.

New frontiers in community initiatives to increase vegetable consumption.

ISSUE ADDRESSED: Public health concerns about insufficient consumption of vegetables across all demographics in Australia have led to 20 years of behaviour change interventions ranging from social marketing to interactive small group programs, with modest results. To maximise health promotion intervention outcomes, practitioners need up-to-date information that helps them navigate the complexity of food systems and eating behaviours. METHODS: This scoping review of Australian and international research, including peer-reviewed and grey literature, provides a picture of health promotion nutrition interventions, as well as other initiatives that may promote increased vegetable consumption. Search terms related to nutrition and vegetable consumption, type of intervention or initiative, for example, campaign; and consumer values and behaviour. A wide range of data sources were used including scholarly papers, market research reports and publicly available websites of community organisations (eg, OOOOBY). A broad food systems typology was developed to provide a framework for the review. RESULTS: The review finds an emerging group of community-driven initiatives within local food systems that appear to have positive impacts on vegetable consumption. These initiatives sit within a multi-faceted approach to health and well-being that is consistent with the tenets of the Ottawa Charter for Health Promotion, including community engagement, social justice and sustainability goals. CONCLUSIONS: More research into the impact of these new frontiers is needed, but our preliminary findings point to the potential for health promotion practitioners to collaborate on local/community food system initiatives that are not motivated primarily by health goals, but have the potential to deliver multiple health and environmental outcomes. SO WHAT?: This review demonstrated community-driven initiatives around local food systems show the most promise in promoting vegetable consumption and addressing the determinants of health. Health promotion efforts to encourage food security and healthy eating could be strengthened through collaborations within these new frontiers.

Minding our futures: Understanding climate-related mental wellbeing using systems science.

INTRODUCTION: Climate change impacts mental wellbeing through complex pathways and young people are among the most vulnerable to climate-related anxiety. Minding our Futures used methods from systems science to explore this issue and identify actions to promote mental wellbeing for young Australians (18-24 years). METHODS: This qualitative study used Group Model Building via three online facilitated workshops recruiting health, youth and climate practitioners and researchers engaged with young people around climate change and/or mental wellbeing (N = 14). Analysis created a systems map and rich description of the relationships between causal factors and their impact on young people. RESULTS: Three themes emerged; "Government, Services and Structures" highlighted underlying structural issues including capitalism and political powerlessness; "Social Norms, Communication and Taking Action" reflected social media and misinformation; and "Personal Experience of Environmental Disasters" described the impact of climate-related disasters and importance of nature and place connection. Participants specified connections between the themes and mental health outcomes. CONCLUSION: This novel applied translational research process supported key informants to design structural responses to a complex and critical public health issue. Their vision was a multi-faceted approach, co-led with young people, drawing on Indigenous knowledges and change-focused policy, community empowerment and nature-based interventions.

Minding environment, minding workers: environmental workers' mental health and wellbeing.

Climate change and environmental degradation caused by human activities are having an irrefutable impact on human health, particularly mental health. People working in the environment sector are confronted with these impacts daily. This exploratory study was conducted as a response to concern in the sector about rising levels of worry and distress, and a need for organizational knowledge about effective workplace mental health strategies. Using evidenced-based frameworks for workplace mental health and wellbeing, the study focused on the relationship between climate change, environmental degradation and mental health issues for this sector. This Australian-based exploratory qualitative study was guided by participatory research approaches. Maximum variation and criterion sampling strategies were applied to engage environmental sector senior managers (n = 8) in individual/paired interviews, followed by online focus group sessions with frontline employees (n = 9). Qualitative thematic analysis techniques were used in an iterative process, combining inductive and deductive strategies. Data was triangulated and interpretation was finalized with reference to literature and a workplace mental health promotion framework. Interview data provided new perspectives on the interconnectivity between risk and protective factors for mental health. Workers were motivated by commitment and values to continue their work despite experiencing increasing levels of trauma, ecological grief, and stress due to overwork and ecological and climate change crises. The findings highlight the need for integrated health promotion approaches that acknowledge the complex interactions between risk and supportive factors that influence mental health in this sector.

Genetic dissection of down syndrome-associated alterations in APP/amyloid-ß biology using mouse models.

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer's disease, in which amyloid-ß accumulates in the brain. Amyloid-ß is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or 'dose' of APP is thought to be the cause of this early-onset Alzheimer's disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aß biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-ß aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer's disease in people who have Down syndrome.