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BackgroundGenetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.MethodsWe engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.ResultsLeveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged.DiscussionOur findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.

Global increases in metabolic disorders such as type 2 diabetes (T2D), especially within Asian populations, highlight the need for novel approaches to dietary intervention. The Tū Ora study previously evaluated the effects on metabolic health of including a nut product into the diet of a New Zealand cohort of Chinese participants with overweight and normoglycaemia or prediabetes through a 12-week randomised, parallel-group clinical trial. In this current study, we compared the impact of this higher-protein nut bar (HP-NB) versus a higher-carbohydrate cereal bar (HC-CB) on the faecal microbiome by employing both 16S rRNA gene amplicon and shotgun metagenomic sequencing of pre- and post-intervention pairs from 84 participants. Despite the higher fibre, protein, and unsaturated fat content of nuts, there was little difference between dietary groups in gut microbiome composition or functional potential, with the bacterial phylum Firmicutes dominating irrespective of diet. The lack of observed change suggests the dietary impact of the bars may have been insufficient to affect the gut microbiome. Manipulating the interplay between the diet, microbiome, and metabolic health may require a more substantial and/or prolonged dietary perturbation to generate an impactful modification of the gut ecosystem and its functional potential to aid in T2D risk reduction. [ABSTRACT FROM AUTHOR]

Every five years and when initially enrolling to vote, Māori have the choice between the Māori roll or the general roll. Research has explored the predictors of roll choice for older adults, but this paper presents the first exploration of roll choice for rangatahi Māori (Māori youth; aged 13–18), and the predictors of rangatahi not understanding the difference between rolls. We draw on Māori data (n = 1528) from Youth19 which surveyed students from a random sample of schools from Tai Tokerau, Tāmaki Makaurau, and Waikato. We find those Māori who also identify as Pākehā (New Zealand European) are less likely to opt for the Māori roll, but those who know their Iwi, are comfortable in Māori social surroundings, feel a spiritual connection to land and the presence of their ancestors in their lives, or feel the drive to be respected as Indigenous, are more likely to choose the Māori roll. Older rangatahi are more likely to say they understand the question, as are those with study plans post-secondary school, and who say they are comfortable in Māori social settings. These results contribute to a body of knowledge valuable for those seeking to increase voter enrolment and enrolment on the Māori roll. Glossary of Māori words: Hapū: kinship group, generally smaller than Iwi; sometimes translated to sub-tribe; hui: meeting; Iwi: broader tribal unit or grouping; nation; kaitiaki: guardian, steward, trustee; kanohi-ki-te-kanohi: face to face/in person; kapa haka: Māori performing arts; traditional performance; Kura Kaupapa Māori: Māori language/Māori medium schools; mana whenua: Māori group(s) who have authority, power, or rights over a certain area of land; marae: meeting house and the area surrounding it; mātauranga Māori: Māori ways of knowing/knowledge; Pākehā: New Zealanders of European descent; rangatahi: youth; rohe: area, region; tangata whenua: Indigenous peoples of Aotearoa New Zealand; people(s) of the land; te reo Māori: the Māori language; te Tiriti o Waitangi: the Māori language version of the Treaty of Waitangi; tīpuna/tupuna: ancestors; waka ama: canoe sport; wānanga: meetings for discussion, deliberation, forums; whanau: family, extended family, or family-like group; whanaungatanga relationship, kinship, sense of family-like connections between people. [ABSTRACT FROM AUTHOR]