Effect of chronic hCG administration on Alzheimer's-related cognition and A beta accumulation in PS1KI mice

Age-associated changes in the reproductive hormones-the gonadal steroid hormones and the gonadotropins-have been identified as potential risk factors for Alzheimer's disease (AD). However, levels of gonadotropins and estrogens are closely linked in vivo, and it has proven difficult to separate the effects of gonadotropins from the well-documented estrogenic effects on AD-related neuropathology in experimental models of menopause. To assess the effects of gonadotropins on cognition and AD biochemical markers independent of estrogenic effects, a potent analog of luteinizing hormone [human chorionic gonadotropin (hCG)] was administered to ovariectomized presenilin1 knock-in mice (PS1KI). Gonadotropin administration was found to induce hyperactivity and anxiety (Open Field Maze and Taste Neophobia Task) and working memory dysfunction, without altering reference memory (Morris Water Maze). Although gonadotropin administration modestly altered β amyloid (Aβ40) levels, levels of the longer more toxic form (Aβ42) were unaffected. Furthermore, altered Aβ40 levels were not associated with observed behavioral and cognitive impairments. These findings provide proof, in principle, that the gonadotropin hormones play a role in the modulation of AD-related behavior, cognition, and neuropathology.