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THE ROLE OF LUTEINIZING HORMONE IN ALZHEIMER DISEASE

Webber, Kate M
http://rave.ohiolink.edu/etdc/view?acc_num=case1164836822

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Pathology.
Epidemiological and experimental evidence suggest that increasing levels of luteinizing hormone (LH) following reproductive senescence may play a role in the development and progression of Alzheimer disease (AD). In this regard, LH is significantly increased in the AD brain, and also has the highest levels of expression in the hippocampus, a key processor of cognition that is deteriorated in AD. Despite increasing evidence for LH-induced AD pathogenesis, little is known about the etiology of LH or the effects of LH binding to its receptor in the brain. Furthermore, leuprolide acetate, an LH-lowering agent, is in clinical trials for the treatment of AD; however, the mechanism behind leuprolide acetate based neuroprotection has yet to be elucidated. In order to identify downstream events of LH binding in the brain, we chose to investigate the expression of steroidogenic acute regulatory protein (StAR) and found increases in the hippocampus of AD brains that colocalized to LH receptor-expressing neurons suggesting that increased LH in AD neurons is responsible for increased StAR in AD. To determine if neuronal LH might be the consequence of endogenous expression, we used RT-PCR, and detected GnRH and LH-β and hCG-β mRNA in non-demented brain. In an expanded study, a significant increase of LH-β mRNA was detected in the AD brain; however, GnRH was not increased using real time RT-PCR. We examined cognitive performance in mice that over-expressed LH (Tg-LH-β) and LH receptor knockout mice (LHRKO) and found that Tg-LH-β mice and heterozygous LHRKO mice demonstrated significant declines in Y-maze performance. In a transgenic mouse model of AD, lowering LH levels by leuprolide acetate administration led to sustained cognitive ability likely reflective of significantly decreased the levels of amyloid-β deposition in these mice. In an additional study, leuprolide acetate decreased LH-β mRNA expression in the pituitary and brain, and increased GnRH mRNA expression in the pituitary yet resulted in decrease of GnRH mRNA expression in the brain. In their entirety, these studies provide novel information regarding LH binding and expression in the AD brain, important links to LH and cognition and an insight into the mechanisms of leuprolide acetate based neuroprotection.
Mark Smith (Advisor)
Health Sciences, Pathology
Alzheimer disease; luteinizing hormone; gonadotropin-releasing hormone; brain-derived hormone expression; steroidogenic acute regulatory protein; leuprolide acetate

Recommended Citations

Citations

  • Webber, K. M. (2007). THE ROLE OF LUTEINIZING HORMONE IN ALZHEIMER DISEASE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1164836822

    APA Style (7th edition)

  • Webber, Kate. THE ROLE OF LUTEINIZING HORMONE IN ALZHEIMER DISEASE. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1164836822.

    MLA Style (8th edition)

  • Webber, Kate. "THE ROLE OF LUTEINIZING HORMONE IN ALZHEIMER DISEASE." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1164836822

    Chicago Manual of Style (17th edition)

case1164836822
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© 2006, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.