Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease.

Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.

A spherical-plot solution to linking acceleration metrics with animal performance, state, behaviour and lifestyle.

BACKGROUND: We are increasingly using recording devices with multiple sensors operating at high frequencies to produce large volumes of data which are problematic to interpret. A particularly challenging example comes from studies on animals and humans where researchers use animal-attached accelerometers on moving subjects to attempt to quantify behaviour, energy expenditure and condition. RESULTS: The approach taken effectively concatinated three complex lines of acceleration into one visualization that highlighted patterns that were otherwise not obvious. The summation of data points within sphere facets and presentation into histograms on the sphere surface effectively dealt with data occlusion. Further frequency binning of data within facets and representation of these bins as discs on spines radiating from the sphere allowed patterns in dynamic body accelerations (DBA) associated with different postures to become obvious. METHOD: We examine the extent to which novel, gravity-based spherical plots can produce revealing visualizations to incorporate the complexity of such multidimensional acceleration data using a suite of different acceleration-derived metrics with a view to highlighting patterns that are not obvious using current approaches. The basis for the visualisation involved three-dimensional plots of the smoothed acceleration values, which then occupied points on the surface of a sphere. This sphere was divided into facets and point density within each facet expressed as a histogram. Within each facet-dependent histogram, data were also grouped into frequency bins of any desirable parameters, most particularly dynamic body acceleration (DBA), which were then presented as discs on a central spine radiating from the facet. Greater radial distances from the sphere surface indicated greater DBA values while greater disc diameter indicated larger numbers of data points with that particular value. CONCLUSIONS: We indicate how this approach links behaviour and proxies for energetics and can inform our identification and understanding of movement-related processes, highlighting subtle differences in movement and its associated energetics. This approach has ramifications that should expand to areas as disparate as disease identification, lifestyle, sports practice and wild animal ecology. UCT Science Faculty Animal Ethics 2014/V10/PR (valid until 2017).

Speech acts and performances of scientific citizenship: Examining how scientists talk about therapeutic cloning.

Scientists play an important role in framing public engagement with science. Their language can facilitate or impede particular interactions taking place with particular citizens: scientists' "speech acts" can "perform" different types of "scientific citizenship". This paper examines how scientists in Australia talked about therapeutic cloning during interviews and during the 2006 parliamentary debates on stem cell research. Some avoided complex labels, thereby facilitating public examination of this field. Others drew on language that only opens a space for publics to become educated, not to participate in a more meaningful way. Importantly, public utterances made by scientists here contrast with common international utterances: they did not focus on the therapeutic but the research promises of therapeutic cloning. Social scientists need to pay attention to the performative aspects of language in order to promote genuine citizen involvement in techno-science. Speech Act Theory is a useful analytical tool for this.

Comparative studies using the Morris water maze to assess spatial memory deficits in two transgenic mouse models of Alzheimer's disease.

Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age-related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA-based 'line 85'-derived double-transgenic mice coexpressing the 'Swedish' mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) 'dE9' mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. ß-Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4-21 months) of single-transgenic genomic-based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and ß-amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.