P1–369: Evidence of gonadotropin–induced steroidogenesis in Alzheimer's disease

Alzheimer's disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual–spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has many questioning the potential role of sex steroids, namely estrogen, in disease pathogenesis. However, while estrogen has become the primary focus of research, inconclusive data regarding estrogen replacement therapy has led some researchers to begin investigating the effects of the other hormones of the hypothalamic–pituitary–gonadal (HPG) axis on the aging brain. Recent studies from our group and others have reported not only a two–fold increase in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases. Furthermore, the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. We examined the expression levels of steroidogenic acute regulatory protein (StAR), a protein involved in cholesterol movement into the mitochondria, the first key event in steroidogenesis. StAR protein is regulated by LH through the cyclic AMP second messenger pathway and is serine phosphorylated by protein kinase A (PKA). PKA has also been demonstrated to activate amyloid precursor protein shedding, a key regulatory step in the generation of amyloid β protein. StAR protein was markedly increased in both the cytoplasm of hippocampal pyramidal neurons as well as in the cytoplasm of other non–neuronal cell types from AD brains when compared with age–matched controls. Generation of steroid hormones by neuronal and glial cells in AD brains may contribute to autocrine/paracrine signaling events within the brain tissue. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression which not only suggests that LH is able to bind to its receptor and induce potentially pathogenic signaling in AD, but also that steroidogenic pathways regulated by LH may play a role in AD. Work in the authors laboratories supported by Voyager Pharmaceutical Corporation, the National Institutes of Health and by the Alzheimer Association.