1 Scientific RepoRts | 7: 2764 | DOI:10.1038/s41598-017-03016-0 www.nature.com/scientificreports environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer’s model Kimberley e. stuart 1 , Anna e. King 1 , Carmen M. Fernandez-Martos 1 , Mathew J. summers 2 & James C. Vickers 1 Cognitive stimulation has been proposed as a non-pharmacological intervention to be used in primary, secondary and tertiary prevention approaches for Alzheimer’s disease. A common familial Alzheimer’s disease transgenic model showed heightened levels of the stress hormone, corticosterone. When exposed to periodic enhanced cognitive stimulation, these animals demonstrated further heightened levels of corticosterone as well as increased Aβ pathology. Hence, Alzheimer’s disease may be associated with hypothalamic-pituitary-adrenal (HpA) axis dysfunction, causing stimulatory environments to become stress-inducing, leading to a glucocorticoid-pathology cycle contributing to further Aβ release and plaque formation. This fnding suggests that stimulation-based interventions and local environments for people with Alzheimer’s disease need to be designed to minimise a stress response that may exacerbate brain pathology. Te ageing of the global population is accompanied by an increasing substantial social and fnancial impact of ageing-related diseases that cause dementia. Among elderly populations, Alzheimer’s disease (AD) is the most common cause of dementia 1 . Research has consistently demonstrated that the environment infuences the brain both structurally and functionally over the lifetime 2 . In this respect, among modifable factors that are associated with a reduced risk of developing dementia, is living a cognitively engaged life. Indeed, those who engage in high levels of cognitive activity have approximately half the risk of developing dementia than those who engage in low levels 3 . Te cognitive reserve theory (CR) posits that a high-level of intellectual engagement over the life promotes strong and efcient neuronal connections that enables the neural system capacity to withstand a greater degree of pathological insult before clinical expression of the disease process emerges 4 . In animal models, the building of cognitive reserve can be modelled experimentally through an environmen- tal enrichment (EE) paradigm. EE describes the manipulation of an animals’ environment in order to generate novelty and complexity, and heighten cognitive, sensory, and physical stimulation 5 . EE applied in early-life has been found to boost cognitive performance in familial AD (FAD) transgenic mouse models to the level of healthy wildtypes (Wt). However, EE is reported to have a variable efect on Aβ pathological burden in transgenic mice expressing human FAD-related gene mutations, with reported decrease 6–8 , no change 9–11 , or increase 12, 13 in Aβ load. Alternatively, it is possible that more complex, and novel stimulation may be required to bufer AD-related neuropathology 3 . Further, individuals are more likely to take up interventions to delay dementia onset in mid- to late-life, or even afer the onset of early symptoms of dementia. In a previous investigation, we demonstrated some benefcial efects of mid-life EE on cognitive function, with no changes to Aβ neuropathological burden in FAD model mice 14 . Terefore, we sought to examine whether added periodic augmentation of more novel stim- ulation (EE+) in FAD animals from mid-life (6 months of age), would produce fndings consistent with previous reports of reduced Aβ burden following EE 6–8 . In order to examine EE in mid to later-life, mice were raised in standard housing (minimal stimulation; SH) conditions until 6 months of age, and then randomly assigned to SH, environmental enrichment (EE) or enhanced environmental enrichment (EE+) conditions, where the animals remained until 12 months of age. Mice in EE lived in a larger cage to that of SH, and enrichment objects were present in the cage (wooden and plastic blocks of difering shapes and sizes, platforms, a ball, running wheel, and a mouse hut). Mice in the EE+ condition lived in EE, but were also exposed to a novel, larger cage three times per 1 Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Tasmania, 7000, Australia. 2 School of Social Sciences, University of the Sunshine Coast, Sippy Downs, Queensland, 4556, Australia. correspondence and requests for materials should be addressed to K.e.S. (email: Kimberley.Stuart@utas.edu.au) Received: 24 November 2016 Accepted: 21 April 2017 Published: xx xx xxxx opeN