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Defining the effects of stress versus hyperarousal on tauopathy in Alzheimer’s disease

Chronic psychologic stress is associated with an enhanced risk of developing Alzheimer’s disease (AD) and stress has been implicated in enhancing hyperphosphorylation of the protein tau in animal models of tauopathy.

Aims

Assess the effects of chronic mild stress versus chronic sleep disruption on pathology in tau transgenic mice.

Excessive wakefulness / arousal, on the other hand has been shown to cause degeneration of brain regions associated with the maintenance of wakefulness (e.g. locus coeruleus, Raphe Nuclei, orexin neurons): these regions are also known to be vulnerable to degeneration in Alzheimer’s disease. However, whether hyperarousal acts similarly or distinctly to stress with regard to the effects on tau pathology has not been investigated.

Therefore, the present project assesses the effects of chronic mild stress (CMS) versus chronic intermittent hyperarousal (CIH) on tau pathology in mice harbouring a human tau transgene which carries a mutation that enhances tau hyperphosphorylation.

The CMS protocol consists of exposure to a series of mild stressors over several weeks, whereas CIH is generated by exposing mice to a novel, stimulating environment during their normal inactive (light) phase. Mice undergo surgery to install electroencephalography/electromyography head-mounts for the assessment of sleep-wake activity (“polysomnography”; PSG). Cognition is also assessed using a spatial learning and memory task. Subsequently, brains will be assessed by immunohistochemistry, and plasma corticosterone and ACTH measured.

The student will learn about current theories underlying AD, tauopathy, behavioural neuroscience and sleep/wake physiology. Techniques learned include the use of transgenic mouse lines, surgery, PSG, cognitive testing in mice, immunohistochemistry and HPLC.

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