期刊论文

【摘要】

Background

Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?

Discussion

Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.

Mechanism

Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.

Summary

We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

【授权许可】

2014 Lathe et al.; licensee BioMed Central Ltd.

【预览】

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【参考文献】

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BMC Geriatrics
Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

Yuri Kotelevtsev³ Alexandra Sapronova² Richard Lathe¹
[1] Pieta Research, PO Box 27069, Edinburgh EH10 5YW, UK;Optical Research Group, Laboratory of Evolutionary Biophysics of Development, Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia;Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Little France, Edinburgh EH16 4TJ, UK
关键词: 25-hydroxycholesterol; Cholesterol; Inflammation; Infection; APOE; Alzheimer; Atherosclerosis;
Others : 855232 DOI : 10.1186/1471-2318-14-36

received in 2013-10-10, accepted in 2014-02-26, 发布年份 2014
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【 摘 要 】

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