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

Stuart, K ORCID: 0000-0002-7872-4231 2017 , 'Environmental enrichment for healthy and Alzheimer’s disease-associated pathological ageing', PhD thesis, University of Tasmania.

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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
(APPSWEPS1dE9) 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 Aβ 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 Aβ 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 Aβ
pathological burden. Conversely, following the complex and novel paradigm in midlife,
AD mice developed exacerbated Aβ 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 Aβ

Item Type: Thesis - PhD
Authors/Creators:Stuart, K
Keywords: Alzheimer’s disease, environmental enrichment, Aβ pathology, cognitive function, stress, Microglia
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Copyright 2016 the Author

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