한빛사논문
- 조회185
Junghee Ha, MD, PhD,1 Go Eun Kwon, MS,2 Yumi Son, BS,1,3 Soo Ah Jang, MD, PhD,1 So Yeon Cho, PhD,1,3 Soo Jin Park, PhD,4 Hyunjeong Kim, PhD,1,5 Jimin Lee, MS,1 Juseok Lee, MD,6 Dongryul Seo,6 Myeongjee Lee, PhD,7 Do Yup Lee, PhD,4 Man Ho Choi, PhD2* and Eosu Kim, MD, PhD1,3,5*
1 Department of Psychiatry, Laboratory for Alzheimer’s Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine,Seoul, Republic of Korea
2 Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
3 Graduate School of Medical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
4 Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Research Institute for Agricultural and Life Sciences, Seoul National University,Seoul, Republic of Korea
5 Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
6 Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
7 Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
* Correspondence: Man Ho Choi, Eosu Kim
Abstract
Aim: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers.
Methods: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7β-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment.
Results: The serum levels of several metabolites, including 7β-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7β-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7β-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7β-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1β, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7β-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively.
Conclusions: Our results suggest that 7β-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7β-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-30)
- 국내 연구진
- 의약학 > 응용의학
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