This project is being conducted in collaboration with:
Hormonal changes associated with ageing have been implicated in the increased risk of developing Alzheimer's disease (AD). Many studies have provided evidence to show that low levels of oestrogen or testosterone increase the risk of developing AD. This effect may be due to these hormones altering the levels of beta amyloid (Aβ), a molecule that is thought to be central to AD pathogenesis.
Sex hormones are under the control of complex feedback loops that involve hormones called gonadotropins. High levels of the gonadotropin luteinizing hormone (LH) have also been implicated in the increased risk of developing AD and in disease pathogenesis.
The clinical significance of LH and the sex hormones and their relative contribution to the pathogenesis of AD remain to be determined. This is an ongoing project that investigates the role of LH in AD pathogenesis and assesses in animal studies the use of gonadotropin lowering agents as a therapeutic strategy for this disease.
In 2004, we published findings showing that LH can increase the production of beta amyloid in neuronal cells.
In a small study of 40 elderly men we have shown that increases in blood levels of LHare associated with increases in blood levels of beta amyloid, providing further evidence the LH can modulate beta amyloid levels. These findings were presented by Dr Giuseppe Verdile at the International Brain Research Organisation (IBRO) world congress of Neuroscience in Melbourne in July 2007 and a manuscript has been submitted for publication to the journal Molecular Psychiatry.
One of our international students, Mr Limbikani Kanyenda, successfully completed his Masters thesis, extending our original findings to investigate the more potent analogue of LH, the pregnancy hormone, hCG. He showed that hCG can influence the metabolism of the parent molecule to beta amyloid, APP, in rats.
In a small pilot study, PhD student Miss Anna Barron has shown that hCG can impair memory in a mouse model for AD. Further work is required to determine if these changes are associated with AD-like pathology and if LH exacerbates pathology in the brains of these mice. In addition these findings require validation in a larger number of mice. Her preliminary findings were presented at the 30th Annual Meeting of the Japan Neuroscience Society in Yokohoma, Japan in July 2007.
We were awarded an NHMRC grant in conjunction with Professor Gary Hulse and Professor Tae Ji to investigate the mechanism(s) involved in LH and hCG mediated changes in beta amyloid production using cell culture and AD animal models. In addition, LH lowering agents will be assessed in an animal model for AD as a therapeutic strategy for treating this disease.
Further human clinical studies to assess the therapeutic efficacy of one of the LH lowering agents is planned to be undertaken by the Clinical Trials Division in the near future.
McCUSKER