Environmental enrichment for healthy and Alzheimer's disease-associated pathological ageing

Interventions to reduce the burden of dementia-causing diseases are urgently needed given global ageing, and the current lack of effective therapeutic approaches. Alzheimer's disease (AD) is a neurodegenerative disease, and the most common cause of dementia among older people, for which there is no known cure, or effective treatment. Engagement in complex cognitive activity can promote an array of neuroplastic mechanisms associated with cognitive protection. Epidemiological evidence suggests a high level of cognitive engagement, particularly in early-life, to be associated with a reduced risk of developing dementia in later-life, including that caused by AD. However, an intervention aimed at preventing or delaying dementia is more likely to be taken up in later-life. Furthermore, limitations inherent in epidemiological investigations means that the mechanisms underlying this putative relationship are not well understood, and the array of extraneous factors that are encountered over a person's life-span cannot be controlled for. In the current study, an environmental enrichment (EE) paradigm was used, in order to experimentally recapitulate the promotion of neural plasticity from experience. The overarching aim of this study was to investigate the effect of EE in healthy ageing, and on AD-associated pathological ageing after the onset of disease-induced pathology, following a non-stimulating early-life. Healthy wildtype (Wt) and transgenic AD (APP\\(_{SWE}\\)PS1\\(_{dE9}\\)) mice were raised in a non-stimulating environment (standard housing; SH) and then randomly assigned back into SH or into EE starting at mid-life (6 months) or later-life (12 months) for a 6-month period. Further, it was aimed to: assess the effect of mid-life EE on hallmark AD neuropathological and structural brain alterations, and how this related to cognitive features, and how this differed to healthy ageing; to investigate the effect of a complex and novel EE paradigm (EE+) on A˜í‚⧠neuropathology; and to examine whether the brains' immune cells, microglia, have a role in the link between EE and cognitive protection in a late-life intervention. The key conclusions drawn from these investigations were that mid-life and later-life EE were not effective interventions in reducing A˜í‚⧠pathological burden in the presence of existing pathology. However, the mid-life EE paradigm was associated with compensatory processes in AD mice, demonstrated by a benefit to short-term memory, an increase in the neurotrophin BDNF in the hippocampus, and an increase in synaptic density in the CA1 subregion of the hippocampus. The EE+ paradigm was introduced to assess whether more complex activity would be associated with reduction to A˜í‚⧠pathological burden. Conversely, following the complex and novel paradigm in midlife, AD mice developed exacerbated A˜í‚⧠neuropathological burden, and demonstrated an increased vulnerability to stress. APP/PS1 mice were found to have an increase in the area occupied by microglia in the hippocampus and neocortex relative to healthy ageing Wt mice, however, late-life EE altered this effect, resulting in no genotype differences. Overall, this investigation demonstrated EE paradigms introduced through mid to later-life for both non-pathological and pathological ageing, are associated with some level of cognitive enhancement. The findings of this thesis suggest the protective effect of EE on cognitive function in a transgenic model of AD pathology, relies on an enhancement of synaptic connectivity and factors that promote neural plasticity, as cognitive protection was observed with no evidence of an attenuation of existing A˜í‚⧠neuropathology.