Changes in Brain Transcripts Related to Alzheimer's Disease in a Model of HFE Hemochromatosis are not Consistent with Increased Alzheimer's Disease Risk

Article type: Research Article

Authors: Johnstone, Daniel M.^{a; b; c; e} | Graham, Ross M.^{f; g; h} | Trinder, Debbie^{f; g} | Riveros, Carlos^{b; c; d} | Olynyk, John K.^{f; g; i; j} | Scott, Rodney J.^{a; b; c} | Moscato, Pablo^{b; c; d} | Milward, Elizabeth A.^{a; b; c; *}

Affiliations: [a] School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia | [b] Hunter Medical Research Institute, New Lambton Heights, NSW, Australia | [c] Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, The University of Newcastle, Callaghan, NSW, Australia | [d] School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia | [e] Bosch Institute and Discipline of Physiology, University of Sydney, NSW, Australia | [f] School of Medicine and Pharmacology, University of Western Australia, Fremantle, WA, Australia | [g] Western Australian Institute for Medical Research, Perth, WA, Australia | [h] School of Biomedical Sciences, Curtin University of Technology, Bentley, WA, Australia | [i] Curtin Health Innovation Research Institute, Curtin University of Technology, Bentley, WA, Australia | [j] Department of Gastroenterology, Fremantle Hospital, Fremantle, WA, Australia

Correspondence: [*] Correspondence to: Dr. Liz Milward, School of Biomedical Sciences and Pharmacy MSB, University of Newcastle, Callaghan, NSW 2308, Australia. Tel.: +61 2 4921 5167; Fax: +61 2 4921 7903; E-mail: [email protected].

Abstract: Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe−/− mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. There were decreases of up to 9-fold in transcripts for amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and various other γ-secretase components, as well as Notch signaling pathway molecules. This included decreased transcripts for ‘hairy and enhancer of split’ Hes1 and Hes5, downstream targets of Notch canonical signaling. The reductions in Hes1 and Hes5 transcripts provide evidence that the changes in levels of transcripts for γ-secretase components and Notch signaling genes have functional consequences. The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe−/− mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading.

Keywords: Amyloid-β protein precursor, γ-secretase, hemochromatosis, HFE, iron, notch signaling

DOI: 10.3233/JAD-2012-112183

Journal: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 791-803, 2012