Aim: 

Hypothalamic-pituitary-gonadal axis dysregulation during menopause/andropause has been related to the cognitive and neuropathological changes observed in Alzheimer's disease (AD). Steroid hormone replacement therapy in early postmenopausal women may decrease the incidence and delay the onset of AD and estrogens are able to modulate b-amyloid (b-A) formation. It has also been suggested that treatments with GnRH, diminishing gonadotropin serum levels, may ameliorate the cognitive behaviour of AD patients. For this reason, we have evaluated whether GnRH may directly affect the expression levels of the amyloid precursor protein (APP) and its converting enzymes BACE1 (that converts APP in b-A), ADAM10 and ADAM17 (that convert APP in non-amyloidogenic peptides), as well as of seladin-1 (SELective Alzheimer Disease INndicator-1) an estrogen-regulated gene, found to be down-regulated in brain areas affected by AD, coding for a protein with enzymatic and anti-apoptotic properties.

Methods: 

The expression of the different genes has been evaluated by RT-qPCR in the neuroblastoma cell line SH-SY5Y.

Results: 

The results show that this cell line expresses GnRH receptor, and that a 24-hour exposure to different concentrations (100 pM–1 mM) of the GnRH agonist leuprolide acetate stimulates the expression of seladin-1, and decreases that of BACE-1. Moreover, in the same experimental conditions the mRNA levels of APP, ADAM10 and ADAM17 were unaffected.

Conclusions: 

these preliminary data suggest that GnRH may exert a direct neuroprotective effect acting on the processing of APP and increasing the expression of seladin-1.

(Grants: MIUR-PRIN, 2006069900_002; FIRST, University of Milan)