A Lead Study on Oxidative Stress-Mediated Dehydroepiandrosterone Formation in Serum: The Biochemical Basis for a Diagnosis of Alzheimer's Disease

Issue title: Drug Discovery for Neurodegenerative Diseases: Challenges and Novel Biochemical Targets

Guest editors: Gabriel B. Britton, Mark A. Smith, George Perry, Kumar Sambamurti and K.S. Jagannatha Rao

Article type: Research Article

Authors: Rammouz, Georges^a | Lecanu, Laurent^{a; b; c} | Aisen, Paul^{d; e} | Papadopoulos, Vassilios^{a; b; c; f; *}

Affiliations: [a] The Research Institute of the McGill University Health Centre, Montreal, QC, Canada | [b] Department of Medicine, McGill University, Montreal, QC, Canada | [c] Department of Biochemistry and Molecular Biology and Cell Biology, Georgetown University Medical Center, Washington, DC, USA | [d] Department of Neurology, Georgetown University Medical Center, Washington, DC, USA | [e] Department of Neurosciences, University of California, San Diego; School of Medicine, La Jolla, CA, USA | [f] Departments of Biochemistry and Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada

Correspondence: [*] Correspondence to: Dr. V. Papadopoulos, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, C10-148, Montreal, Quebec H3G 1A4, Canada. Tel.: 514 934 1934, ext 44580; Fax: 514 934 8439; Email: [email protected].

Abstract: Alzheimer's disease (AD) is a progressive, yet irreversible, neurodegenerative disease for which there are limited means for its ante-mortem diagnosis. We previously identified a brain- and cell-specific oxidative stress-mediated mechanism for dehydroepiandrosterone (DHEA) biosynthesis present in rat, bovine, and human brain, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and amyloid-β peptide. Using brain tissue specimens from control and AD patients we subsequently provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting the levels of the precursor present in the blood stream. Here, we tested for the presence of this DHEA precursor in human serum using a simple Fe2+-based reaction and determined the amounts of DHEA formed. A total of 86 subjects were included in this study: 19 male and 20 female AD patients; 18 male and 22 female age-matched controls; and 4 men and 3 women with mild cognitive impairment. Serum oxidation resulted in a dramatic increase of DHEA level in control patients, whereas only a moderate or no increase was observed in the AD patients. The DHEA variation after oxidation correlated with the patients' cognitive and mental status. These results suggest that the comparison of DHEA levels in patient serum before and after oxidation could provide a useful tool to diagnose AD.

Keywords: Alzheimer's disease, blood, DHEA, diagnosis, gas chromatography, mass spectrometry, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2011-101941

Journal: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 5-16, 2011