Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease

Abstract

Background: Alzheimer 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 led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases 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 as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. However, while LH is higher in AD patients, the downstream consequences of this are incompletely understood. To begin to examine this issue, here, we examined the expression levels of steroidogenic acute regulatory (StAR) protein, which regulates the first key event in steroidogenesis, namely, the transport of cholesterol into the mitochondria, and is regulated by LH through the cyclic AMP second messenger pathway, in AD and control brain tissue.

Results: Our data revealed that 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. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression.

Conclusion: Therefore, our findings suggest that LH is not only 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.

Figure 1

The immunolocalization of StAR. Immunocytochemical localization of StAR in AD-affected individuals is increased in pyramidal hippocampal neurons as well as in astrocytes (Panel A) in comparison to age-matched control brains (Panel B). Scale bar for panels A and B = 50 μm. Scale bar within the inset in Panel A = 25 μm.

Figure 2

Absorption verifies the specificity of antibody binding. Staining in the hippocampus with StAR in AD (Panel A) is decreased by absorption with the immunizing peptide (Panel B). Scale bar = 50 μm.

Figure 3

Immunocytochemical analysis of the distribution of StAR and hLH/CG receptor. Adjacent serial hippocampal sections of an AD patient show overlap between StAR immunolocalization (Panel A) and hLH/CG receptor immunolocalization (Panel B). Arrows point to neurons included in both hippocampal sections that show positive immunoreactivity for StAR and LH receptor. Asterisk denotes landmark vessel. Scale bar = 50 μm.

Figure 4

Schematic of LH action in AD. Upon binding to its receptor on neurons and/or glial cells within the brain, LH potentially induces signaling cascades that result in increased StAR expression and possibly subsequent increases in steroidogenesis via autocrine or paracrine signaling mechanisms.