Abstract
BackgroundAging 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?DiscussionBoth 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.MechanismInfection 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.SummaryWe 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.
Highlights
Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD)
We present evidence that chronic macrophage cholesterol 25-hydroxylase (CH25H) upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of Acyl-CoA cholesterol acyltransferase (ACAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease
In a group of 53 AD patients, H. pylori infection was significantly associated with reduced cognitive ability and higher CSF Tau [183] and, in the most recent study, in which 600 elderly individuals were followed for a period of 19 years, H. pylori infection determined by serology was found to be a risk factor for developing dementia [184]
Summary
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?. Better nutrition and lifestyle changes make important contributions to extending human lifespan, but new morbidities are encountered with aging, notably AD and ATH. At first sight these appear to be different conditions. In the present debate we address whether the two conditions are different, or instead share a common condition, both crucially linked to sterol metabolism and innate immunity, leading to vascular occlusion
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