Metabolomic Signatures in Peripheral Blood Associated with Alzheimer's Disease Amyloid-β-Induced Neuroinflammation

Article type: Research Article

Authors: Kim, Eosu^{a; b; 1} | Jung, Young-Sang^{d; 1} | Kim, Hyunjeong^{a; b} | Kim, Jin-Sup^d | Park, Minsun^a | Jeong, Jihyeon^{a; b} | Lee, Su Kyoung^a | Yoon, Ho-Geun^{b; c} | Hwang, Geum-Sook^{d; e; *} | Namkoong, Kee^{a; *}

Affiliations: [a] Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea | [b] Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea | [c] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea | [d] Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea | [e] Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea

Correspondence: [*] Correspondence to: Kee Namkoong, Department of Psychiatry, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel.: +82 2 2228 1620; Fax: +82 2 313 0891; E-mail: keen@yuhs.ac; Geum-Sook Hwang, Integrated Metabolomics Research Group, Korea Basic Science Institute, 126-16, 5th St. Anam-dong, Seongbuk-gu, Seoul 137-713, Korea. Tel.: +82 2 6943 4137; Fax: +82 2 920 0709; E-mail: gshwang@kbsi.re.kr.

Note: [1] These authors contributed equally to this work.

Abstract: Discovery of biomarkers in peripheral blood is a crucial step toward the early diagnosis and repetitive monitoring of treatment response for Alzheimer's disease (AD). Metabolomics is a promising technology that can identify unbiased biomarkers. To explore potential blood biomarkers for AD via metabolic profiling with high-resolution magic angle spinning nuclear magnetic resonance techniques, we identified changes in peripheral blood metabolomic profiles in response to amyloid-β (Aβ)-induced neuroinflammation and co-treatment with gallate, a phytochemical known to have anti-neuroinflammatory properties. Alzheimer's-like (AL) model mice were produced by intracerebroventricular infusion of Aβ and compared with normal control mice with infusion of vehicle. AL mice were treated with either gallate (treated AL mice) or vehicle (untreated AL mice). Metabolomic analyses of both whole blood and plasma showed a clear separation between untreated AL mice and the other two groups, with levels of several metabolites involved in energy metabolism, including pyruvate and creatine, being significantly reduced in untreated AL mice compared with control and treated AL mice. Gallate treatment suppressed Aβ-induced overproduction of the inflammatory cytokine tumor necrosis factor-α in the hippocampus and normalized plasma levels of the affected metabolites. These results suggest that plasma levels of several metabolites could be indicative of both brain pathology and therapeutic responses, supporting the possibility of a close relationship between central neuroinflammation and systemic metabolic disturbance. These findings also suggest the potential of NMR-based metabolomics as a method to identify novel plasma biomarkers for AD, which could be confirmed by future translational research with human patients.

Keywords: Alzheimer's disease, biomarker, creatine, metabolomics, neuroinflammation, NMR, plasma, pyruvate

DOI: 10.3233/JAD-132165

Journal: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 421-433, 2014