Beta amyloid expression or lack of sex hormones results in brain pathology associated with Alzheimer's disease

Eleanor Drummond

    Research output: ThesisDoctoral Thesis

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    Abstract

    [Truncated abstract] Extensive research has linked many risk factors with the onset and progression of Alzheimer’s disease (AD). However, the mechanism of how these risk factors promote AD brain pathology is not yet understood. Research presented in this thesis examined how two such risk factors linked to AD; depletion of sex hormones and beta amyloid (Aβ) over-expression, were associated with the development of molecular brain changes observed in AD using two animal models novel to the AD field. The depletion of estrogens and androgens and the consequent increase in gonadotropins with age has been shown to promote AD brain pathology and is associated with decline in cognitive function. However, how altered levels of sex hormones promote pathology and which sex hormone is primarily responsible for the AD associated brain changes is still under investigation. Research presented in Chapters 2 and 3 examined the AD associated molecular changes in the brain of aged hypogonadal (hpg) mice. Hpg mice have a naturally occurring genetic mutation in the gene for gonadotropin releasing hormone that results in life-long low levels of circulating sex hormones and gonadotropins. Depletion of sex hormones resulted in decreased levels of amyloid precursor protein (APP) and high levels of presenilin 1, APP C-terminal fragment and Aβ42 in aged male, but not aged female hpg mice. Furthermore, these protein changes were only observed in the hippocampus and not in other brain regions. Aged male hpg mice also had decreased levels of choline acetyltransferase per neuron in the basal forebrain and a strong trend for decreased levels of interleukin 1β. The presence of these AD associated brain changes specifically in male hpg mice suggests that the depletion of androgens may have a significant role in the development of AD pathology. Brain injury is another risk factor associated with AD and sex hormones are considered to be neuroprotective after injury.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2011

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