The gonadotropin connection in Alzheimer’s disease

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• 作者：Sivan Vadakkadath Meethal (1)
  Mark A. Smith (2)
  Richard L. Bowen (3)
  Craig S. Atwood PhD (1) (2)
  
• 关键词：Gonadotropin ; GnRH ; sex steroids ; Alzheimer’s disease ; amyloid precursor protein ; tau ; neuron brain ; cell cycle ; HPG axis
• 刊名：Endocrine
• 出版年：2005
• 出版时间：April 2005
• 年：2005
• 卷：26
• 期：3
• 页码：317-325
• 全文大小：163KB
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• 作者单位：Sivan Vadakkadath Meethal (1)
  Mark A. Smith (2)
  Richard L. Bowen (3)
  Craig S. Atwood PhD (1) (2)
  
  1. Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison and Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, 53705, Madison, WI
  2. Institute of Pathology, Case Western Reserve University, 44106, Cleveland, OH
  3. Voyager Pharmaceutical Corporation, 27615, Raleigh, NC
  

文摘

Although not traditionally thought of as regulators of neuronal function, the hypothalamic-pituitary-gonadal (HPG) hormones luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins possess neuronal receptors. These receptors are found throughout the limbic system on a number of different cell types, and, like reproductive tissues, the expression of these receptors is regulated by hormonal feedback loops. These hormones and their receptors regulate structure and a diverse range of functions in the brain. Therefore, it is not surprising that the dysregulation of the HPG axis with menopause and andropause (leading to elevated LH, GnRH, and activin signaling but decreased sex steroid signaling) might promote alterations in both the structure and function of neuronal cells. To date, most evidence has accumulated for a role of LH in promoting neurodegenerative changes. LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer’s disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects. LH promotes the amyloidogenic processing of the amyloid-β precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice. Moreover, leuprolide acetate improves the cognitive performance and decreases amyloid-β deposition in aged transgenic mice carrying the Swedish AβPP mutation. Therefore, the elevation of LH with the dysregulation of the HPG axis at menopause and andropause is a physiologically relevant signal that could promote neurodegeneration. Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists. Clinical trials are underway for the treatment of AD using GnRH analogs and should provide further insights into the gonadotropin connection in AD.