Reduced expression of the cystic fibrosis transmembrane conductance regulator gene in the hypothalamus of patients with Alzheimer's disease

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a similar to 150-165 kD glycoprotein that is mutated in individuals with cystic fibrosis. Previous studies demonstrated expression of the CFTR gene in the hypothalamus, suggesting a potential role for this molecule in the regulation of systemic metabolic functions. Individuals with cystic fibrosis often exhibit wasting and marked reductions in body fat content. Since the hypothalamus is a late target of neurodegeneration in Alzheimer's disease (AD), we postulated that patients with end-stage AD and bodily wasting would have reduced levels of CFTR expression in the hypothalamus. Methods: CFTR mRNA and protein were examined in postmortem hypothalamic tissue from 11 AD and 7 aged controls using in situ hybridization and immunohistochemical staining. Standardized sections that included the supra-optic, paraventricular, anterior, and ventromedial nuclei, and the lateral hypothalamus were studied. Results: The density of CFTR+ neurons and the intensity of the CFTR hybridization signals were strikingly reduced in AD. Immunohistochemical staining studies demonstrated CFTR immunoreactivity most prominently distributed in small clusters of neurites (5 to 20 in number). Digital image quantification showed that the density of CFTR+ neurites was significantly reduced in AD relative to aged control samples (P = 0.001). However, there was no evidence for selective involvement of particular hypothalamic nuclei. Conclusions: CFTR gene expression is down-regulated and its corresponding immunoreactivity reduced in AD relative to control hypothalamic tissue. Reduced CFTR expression in the hypothalamus may represent an important mechanism by which AD neurodegeneration contributes to body wasting in the late stages of disease. Supported by NIH Grants CA-35711, AA-02666, Pathobiology Training Grant from the National Institute for Environmental Health Sciences, an NIH COBRE award (P20RR15578), Panacea Pharmaceuticals, Nymox, and SciClone.